[go: up one dir, main page]

WO2008103351A2 - Inhibiteurs de la protéase d'aspartyle hétérocycliques - Google Patents

Inhibiteurs de la protéase d'aspartyle hétérocycliques Download PDF

Info

Publication number
WO2008103351A2
WO2008103351A2 PCT/US2008/002182 US2008002182W WO2008103351A2 WO 2008103351 A2 WO2008103351 A2 WO 2008103351A2 US 2008002182 W US2008002182 W US 2008002182W WO 2008103351 A2 WO2008103351 A2 WO 2008103351A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
solvate
tautomer
stereoisomer
Prior art date
Application number
PCT/US2008/002182
Other languages
English (en)
Other versions
WO2008103351A3 (fr
Inventor
Zhaoning Zhu
Brian Mckittrick
Zhong-Yue Sun
Yuanzan C. Ye
Johannes H. Voigt
Corey Strickland
Elizabeth M. Smith
Andrew Stamford
William J. Greenlee
Jr. Robert D. Mazzola
John Caldwell
Jared N. Cumming
Lingyan Wang
Yusheng Wu
Ulrich Iserloh
Xiaoxiang Liu
Ying Huang
Guoqing Li
Jianping Pan
Jeffrey A. Misiaszek
Tao Guo
Thuy X. H. Le
Kurt W. Saionz
Suresh D. Babu
Rachael C. Hunter
Michelle L. Morris
Huizhong Gu
Gang Qian
Dawit Tadesse
Gaifa Lai
Jingqi Duo
Chuanxing Qu
Yuefei Shao
Original Assignee
Schering Corporation
Pharmacopeia, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39511364&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008103351(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to RU2009135277/04A priority Critical patent/RU2496774C2/ru
Priority to NZ579301A priority patent/NZ579301A/en
Priority to DK08714220.4T priority patent/DK2097387T3/en
Priority to SI200831653A priority patent/SI2097387T1/sl
Priority to MX2009009063A priority patent/MX2009009063A/es
Priority to ES08714220.4T priority patent/ES2582367T3/es
Priority to AU2008219071A priority patent/AU2008219071B2/en
Priority to MEP-2016-142A priority patent/ME02528B/fr
Application filed by Schering Corporation, Pharmacopeia, Inc. filed Critical Schering Corporation
Priority to CN200880013100.0A priority patent/CN101715442B/zh
Priority to HRP20160876TT priority patent/HRP20160876T1/hr
Priority to HK09108902.1A priority patent/HK1130792B/en
Priority to CA2678958A priority patent/CA2678958C/fr
Priority to LTEP08714220.4T priority patent/LT2097387T/lt
Priority to EP08714220.4A priority patent/EP2097387B1/fr
Priority to BRPI0807547-6A2A priority patent/BRPI0807547A2/pt
Priority to RS20160558A priority patent/RS54979B1/sr
Priority to JP2009550601A priority patent/JP5340177B2/ja
Publication of WO2008103351A2 publication Critical patent/WO2008103351A2/fr
Publication of WO2008103351A3 publication Critical patent/WO2008103351A3/fr
Priority to ZA2009/05837A priority patent/ZA200905837B/en
Priority to IL200561A priority patent/IL200561A/en
Priority to CY20161100753T priority patent/CY1117946T1/el

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin

Definitions

  • This invention relates to heterocyclic aspartyl protease inhibitors, pharmaceutical compositions comprising said compounds, their use in the treatment of cardiovascular diseases, cognitive and neurodegenerative diseases, and their use as inhibitors of the Human' Immunodeficiency Virus, plasmepsins, cathepsin D and protozoal enzymes.
  • renin-angiotensin system (RAS) in regulation of blood pressure and fluid electrolyte has been well established (Oparil, S, etal. N Engl J Med 1974; 291 :381 -401 /446-57).
  • the octapeptide Angiotensin-ll a potent vasoconstrictor and stimulator for release of adrenal aldosterone, was processed from the precursor decapeptide Angiotensin-I, which in turn was processed from angiotensinogen by the renin enzyme.
  • Angiotensin-ll was also found to play roles in vascular smooth muscle cell growth, inflammation, reactive oxygen species generation and thrombosis, influence atherogenesis and vascular damage.
  • AD Alzheimer's disease
  • connective tissue disease connective tissue disease
  • muscular dystrophy muscular dystrophy
  • breast cancer a progressive neurodegenerative disease that is ultimately fatal.
  • Disease progression is associated with gradual loss of cognitive function related to memory, reasoning, orientation and judgment.
  • Behavioral changes including confusion, depression and aggression also manifest as the disease progresses.
  • the cognitive and behavioral dysfunction is believed to result from altered neuronal function and neuronal loss in the hippocampus and cerebral cortex.
  • the currently available AD treatments are palliative, and while they ameliorate the cognitive and behavioral disorders, they do not prevent disease progression.
  • AD extracellular ⁇ -amyloid
  • a ⁇ extracellular ⁇ -amyloid
  • APP amyloid precursor protein
  • a ⁇ peptides result from the cleavage of APP by ⁇ -secretase at the position corresponding to the N-terminus of A ⁇ , and at the C- terminus by ⁇ -secretase activity.
  • APP is also cleaved by ⁇ -secretase activity resulting in the secreted, non-amyloidogenic fragment known as soluble APP.
  • BACE-1 An aspartyl protease known as BACE-1 has been identified as the ⁇ -secretase activity responsible for cleavage of APP at the position corresponding to the N- terminus of A ⁇ peptides.
  • BACE-1 An aspartyl protease known as BACE-1 has been identified as the ⁇ -secretase activity responsible for cleavage of APP at the position corresponding to the N- terminus of A ⁇ peptides.
  • a ⁇ has been shown to be toxic to neuronal cells in vitro and when injected into rodent brains.
  • inherited forms of early-onset AD are known in which well-defined mutations of APP or the presenilins are present. These mutations enhance the production of A ⁇ and are considered causative of AD.
  • inhibition of BACE-1 should inhibit formation of A ⁇ peptides.
  • inhibition of BACE-1 is a therapeutic approach to the treatment of AD and other cognitive and neurodegenerative diseases caused by A ⁇ plaque deposition.
  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • compounds such as indinavir, ritonavir and saquinavir which are inhibitors of the HIV aspartyl protease result in lowering of viral load.
  • the compounds described herein would be expected to be useful for the treatment of AIDS.
  • HIV-1 protease an aspartyl protease related to renin.
  • HTLV-I Human T-cell leukemia virus type I
  • HTLV-I Human T-cell leukemia virus type I
  • HTLV-I Like other retroviruses, HTLV-I requires an aspartyl protease to process viral precursor proteins, which produce mature virions. This makes the protease an attractive target for inhibitor design.
  • Plasmepsins are essential aspartyl protease enzymes of the malarial parasite.
  • the present invention relates to compounds having the structural formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or ester thereof, wherein
  • R 1 , R 2 and R 5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, -OR 15 , -CN, -C(O)R 8 , -C(O)OR 9 , -S(O)R 10 , -S(O) 2 R 10 , -C(O)N(R 11 XR 12 ), -S(O)N(R 11 )(R 12 ), -S(O) 2 N(R 11 )(R 12 ),
  • R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -O-Si(R 9 )(R 10 )(R 19 ), -SH, -CN, -OR 9 , -C(O)R 8 , -C(O)OR 9 , -C(O)N(R 11 KR 12 ), -SR 19 , -S(O)N(R 11 )(R 12 ), -S(O) 2 N(R 11 )(R 12 ), -N(R 11 )(R 12 ), -N(R 11 )C(O)R 8 , -N(R 11 JS(O)R 10 , -N(R 11
  • M is -CH 2 -, S, -N(R 19 )- or O
  • a and B are independently aryl or heteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be a carbon atom and when q is 2, M is optionally a double bond; and with the proviso that when R 3 , R 4 , R 6 and R 7 form said multicyclic groups
  • R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR 15 , -N(R 15 )(R 16 ), -N(R 15 )C(O)R 16 , -N(R 15 )S(O)R 16 , -N(R 15 )S(O) 2 R 16 , -N(R 15 )S(O) 2 N(R 16 )(R 17 ), -N(R 15 )S(O)N(R 16 )(R 17 ), -N(R 15 )C(O)N(R 16 )(R 17 ) and -N(R 15 )C(O)OR 16 ;
  • R 9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
  • R 10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and -N(R 15 )(R 16 );
  • R 11 , R 12 and R 13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)R 8 , -C(O)OR 9 , -S(O)R 10 , -S(O) 2 R 10 , -C(O)N(R 15 )(R 16 ), -S(O)N(R 15 XR 16 ), -S(O) 2 N(R 15 XR 16 ) and -CN;
  • R 15 , R 16 and R 17 are
  • R 23 numbers O to 5 substituents, m is O to 6 and n is 1 to 5;
  • R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, -NO 2 , halo, heteroaryl, HO- alkyoxyalkyl, -CF 3 , -CN, alkyl-CN, -C(O)R 19 , -C(O)OH, -C(O)OR 19 , -C(O)NHR 20 , -C(O)NH 2 , -C(O)NH 2 -C(O)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR 19 , -S(O) 2 R 20 , -S(O)NH 2 , -S(O)NH(alkyl), -S(O)N(alkyl)(alky
  • R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
  • R 20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyclo
  • R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one
  • R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, -NO 2 , halo, -CF 3 , -CN, alkyl-CN, -C(O)R 28 , -C(O)OH, -C(O)OR 28 , -C(O)NHR 29 , -C(O)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR 28 , -S(O) 2 R 29 , -S(O)NH 2 , -S(O)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), -S(O) 2 NH 2 , -S(O) 2 NHR 28 , -S(O) 2 NH(aryl), -S(
  • R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl
  • R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; provided that when W is -C(O)- and U is a bond, R 1 is not optionally substituted phenyl, and that when U is -C(O)- and W is a bond, R 5 is not optionally substituted phenyl; provided that neither R 1 nor R 5 is -C(O)-alkyl-azetidinone or alkyl di-substituted with (-COOR 15 or -C(O)N(R 15 )(R 16 )) and (-N(R 15 )(R 16 ), -N(R 15 )C(O)R 16 , -N(R 15 )S(O)R 16 , -N(R 15 )S(O) 2 R 16 , -N(R 15 )S(O) 2 N(R 16 )(R 17 ), -N(R
  • R 3 and R 4 are alkyl
  • R 21 is halo, -CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R 3 and R 4 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group, and R 1 is
  • R 21a is not H, -C(O) 2 R 15 , wherein R 15 is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R 22 , wherein R 22 is selected from the group consisting of phenyl, phenyl substituted with alkyl,
  • R 22 is selected from the group consisting of H, methoxy, nitro, oxo, -OH, halo and alkyl,
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I and a pharmaceutically acceptable carrier.
  • the invention comprises the method of inhibiting aspartyl protease comprising administering at least one compound of formula I to a patient in need of such treatment.
  • the invention comprises: the method of treating a cardiovascular disease such as hypertension, renal failure, or a disease modulated by renin inhibition; the method of treating Human Immunodeficiency Virus; the method of treating a cognitive or neurodegenerative disease such as Alzheimer's Disease; the method of inhibiting plasmepins I and Il for treatment of malaria; the method of inhibiting Cathepsin D for the treatment of Alzheimer's Disease, breast cancer, and ovarian cancer; and the method of inhibiting protozoal enzymes, for example inhibition of Plasmodium falciparnum, for the treatment of fungal infections.
  • Said method of treatment comprise administering at least one compound of formula I to a patient in need of such treatment.
  • the invention comprises the method of treating Alzheimer's disease comprising administering at least one compound of formula I to a patient in need of such treatment.
  • the invention comprises the method of treating Alzheimer's disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula I and a cholinesterase inhibitor or a muscarinic mi agonist or m 2 antagonist.
  • the invention relates to a kit comprising in separate containers in a single package pharmaceutical compositions for use in combination, in which one container comprises a compound of formula I in a pharmaceutically acceptable carrier and a second container comprises a cholinesterase inhibitor or a muscarinic mi agonist or m 2 antagonist in a pharmaceutically acceptable carrier, the combined quantities being an effective amount to treat a cognitive disease or neurodegenerative disease such as Alzheimer's disease.
  • U is preferably a bond or -C(R 6 )(R 7 )-.
  • U is preferably -C(O)-.
  • R 1 is the same as the definition of R 5 , when X is -N(R 5 )-, compounds of formula I wherein W is a bond and U is a bond, -S(O)-, -S(O) 2 -, -C(O)-, -O-, -C(R 6 )(R 7 )- or -N(R 5 )- are equivalent to compounds of formula I wherein U is a bond and W is a bond, -S(O)-, -S(O) 2 -, -C(O)-, -O-, -C(R 6 XR 7 )- or -N(R 5 )-.
  • More preferred compounds of the invention are those of formula IB wherein U is a bond or those of formula IB wherein U is -C(R 6 )(R 7 )-.
  • R 3 , R 4 , R 6 and R 7 are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -O-Si(R 9 )(R 10 )(R 19 ), -SH, -CN, -OR 9 , -C(O)R 8 , -C(O)OR 9 , -C(O)N(R 11 XR 12 ), -SR 19 , -S(O)N(R 11 )(R 12 ), -S(O) 2 N(R 11 )(R 12 ), -N(R 11 )(R 12 ), -N(R 11 )C(O)R 8 , -N(R 11 )
  • R 3 , R 4 , R 6 and R 7 are preferably selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.
  • U is a bond or -C(O)-;
  • W is a bond or -C(O)-;
  • X is -N(R 5 )-;
  • R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,
  • R 2 is H;
  • R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
  • R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
  • R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl;
  • R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
  • R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
  • R 15 R 16 and R 17 is H, R 18 -alkyl, alkyl or
  • R ⁇ 2'1 1 i,s alkyl, aryl, halo, -OR i1 1 5 0 , -NO 2 , -C(O)R 15 , -CH 2 -N(R >1 1 5 0 ⁇ )C(O)N(R i1 1 6 0 ⁇ )(/rR-,1 1 7' ⁇ ) or
  • R 18 is -OR 20
  • R 20 Is aryl
  • R 23 is alkyl
  • R 3 , R 4 , R 6 and R 7 are preferred compounds.
  • U is a bond or -C(O)-
  • W is a bond or -C(O)-
  • X is -N(R 5 )-
  • R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,
  • R 2 is H
  • R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
  • R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
  • R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl;
  • R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
  • R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
  • R 15 , R 16 and R 17 is H, cycloalkyl, cycloalkylalkyl, R 18 -alkyl, alkyl, aryl, R 18 -aryl,
  • R 18 -arylalkyl, arylalkyl, n is 1 or 2; m is O oM ;
  • R 18 is -OR 20 or halo;
  • R 20 is aryl or halo substituted aryl;
  • R 21 is alkyl, aryl, heteroaryl, R 22 -alkyl, R 22 -aryl, R 22 -heteroaryl, halo, heterocycloalkyl, -N(R 15 )(R 16 ), -OR 15 , -NO 2 , -C(O)R 15 , -N(R 15 )C(O)R 16 , -N(R 15 )S(O) 2 R 16 , -CH 2 -N(R 15 )C(O)N(R 16 )(R 17 ), -N(R 15 )C(O)N(R 16 )(R 17 ) or -CH(R 15 KR 16 ); R 22 is -OR 15 or halo and
  • R ⁇ »2"3 is H or alkyl.
  • carbons of formula I may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.
  • alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n- pentyl, heptyl, nonyl and decyl.
  • R 21 -substituted alkyl groups include fluoromethyl, trifluoromethyl and cyclopropylmethyl .
  • “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • Lower alkenyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. •
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more substituents (e.g., R 18 , R 21 ' R 22 , etc.) which may be the same or different, and are as defined herein or two substituents on adjacent carbons can be linked together to form .
  • substituents e.g., R 18 , R 21 ' R 22 , etc.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one to eight of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more R 21 substituents which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more R 21 substituents which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non- limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like. Further non-limiting examples of cycloalkyl include the following
  • Cycloalkylether means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond.
  • the cycloalkenyl ring can be optionally substituted with one or more R 21 substituents which may be the same or different, and are as defined above.
  • Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • Non- limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1 ,2,3,4- tetrahydropyridine, 1 ,2-dihydropyridyl, 1 ,4-dihydropyridyl, 1 ,2,3,6- tetrahydropyridine, 1 ,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, and the like.
  • suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like.
  • Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
  • suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • Halo means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
  • Haloalkyl means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
  • Heterocyclyl (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3, preferably 1 or 2 of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclyl can be optionally substituted by one or more R 21 substituents which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S 1 S- dioxide.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,3- dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Arylcycloalkyl means a group derived from a fused aryl and cycloalkyl as defined herein.
  • Preferred arylcycloalkyls are those wherein aryl is phenyl and cycloalkyl consists of about 5 to about 6 ring atoms.
  • the arylcycloalkyl can be optionally substituted by 1-5 R 21 substituents.
  • suitable arylcycloalkyls include indanyl and 1,2,3,4-tetrahydronaphthyl and the like.
  • the bond to the parent moiety is through a non-aromatic carbon atom.
  • Arylheterocycloalkyl means a group derived from a fused aryl and heterocycloalkyl as defined herein.
  • Preferred arylcycloalkyls are those wherein aryl is phenyl and heterocycloalkyl consists of about 5 to about 6 ring atoms.
  • the arylheterocycloalkyl can be optionally substituted by 1-5 R 21 substituents.
  • suitable arylheterocycloalkyls include
  • heteroarylalkyl means a heteroaryl-, cycloalkyl- or heterocycloalkyl-alkyl- group in which the heteroaryl, cycloalkyl, heterocycloalkyl and alkyl are as previously described. Preferred groups contain a lower alkyl group.
  • the bond to the parent moiety is through the alkyl.
  • acyl means an H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)- or cycloalkyl-C(O)- group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkyoxyalkyl means a group derived from an alkoxy and alkyl as defined herein. The bond to the parent moiety is through the alkyl.
  • Arylalkenyl means a group derived from an aryl and alkenyl as defined herein. Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms. The arylalkenyl can be optionally substituted by one or more R 27 substituents. The bond to the parent moiety is through a non- aromatic carbon atom.
  • Arylalkynyl means a group derived from a aryl and alkynyl as defined herein. Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more R substituents. The bond to the parent moiety is through a non-aromatic carbon atom.
  • Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group.
  • a variable appears more than once in a group e.g., R 8 in -N(R 8 ) 2
  • a variable appears more than once in the structure of formula I e.g., R 15 may appear in both R 1 and R 3
  • the variables can be the same or different.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the wavy line 'vwx, as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry.
  • Lines drawn into the ring systems such as, for example: indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.
  • R 21 and R 22 are, for example, -N(R 15 )C(O)N(R 16 )(R 17 ) and R 15 and R
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof.
  • prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 -Ci2)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbony
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC 6 )alkanoyloxymethyl, 1-((Ci- C 6 )alkanoyloxy)ethyl, 1-methyl-1-((Ci-C 6 )alkanoyloxy)ethyl, (C 1 - C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylaminomethyl, succinoyl, (Cr C ⁇ jalkanoyl, ⁇ -amino(CrC 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)alkanoyloxymethyl, 1-((Ci- C 6
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Ci O )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (C r C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (d-C ⁇ Jalkyl, carboxy (CrC 6 )alkyl, amino(Ci-C 4 )alkyl or mono-N — or di-
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical ScL, 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(D, article 12 (2004); and A. L. Bingham et al, Chem. Comm ⁇ n., 603-604 (2001).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting aspartyl protease and/or inhibiting BACE-1 and thus producing the desired therapeutic effect in a suitable patient.
  • the compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salts when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge ef a/, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D. C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.
  • Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • organic bases for example, organic amines
  • benzathines diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides
  • esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci -4 alkyl, or C- ⁇ alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphoric acid
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Moshei ⁇ s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Moshei ⁇ s acid chloride
  • the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyi and 3-pyridyl).
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.
  • the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can beheterocyclic aspartyl protease inhibitors.
  • pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore- said "more than one pharmaceutically active agents".
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • MP-TsOH resin Microporous Toluene sulfonic acid resin
  • PS-trisamine tris-(2-aminoethyl)aminomethyl polystyrene
  • PS-NCO Microporous Toluene sulfonic acid resin
  • the compounds in the invention may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below.
  • the tables contain the compounds with observed m/e values from mass spectroscopy and/or NMR data. These compounds can be obtained with synthetic methods similar to these listed in the last column using appropriate reagents.
  • Polystyrene isocyanate resin 45 mg, 3 eq
  • polystyrene trisamine resin 40 mg, 6 eq
  • a 1 :1 mixture of CH 3 CNTHF 0.5 ml_
  • the mixture was agitated for 6 h.
  • -Z-NH-C(O)R 16 - is equivalent to R 1 substituted by R 21 , or R 1 Subsitituted by alkyl-R 22 , wherein R 21 and R 22 are -N(R 15 )C(O)R 16 and R 15 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene-arylene- alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene- cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)
  • R 1 Subsitituted by alkyl-R 22 , wherein R 21 and R 22 are -N(R 16 )-C(O)-NHR 15 and R 16 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene- arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene- heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)
  • the following compounds were prepared using similar methods:
  • the following compounds were prepared using similar methods:
  • the reaction mixture was stirred at room temperature overnight before it was partitioned between ether and saturated NaHCO 3 water solution.
  • the aqueous phase was extracted with ether 2 times.
  • the combined organic phase was washed with brine 2 times, and dried over anhydrous NaSO 4 .
  • the reaction mixture was stirred at room temperature overnight under N 2 before the solid was filtered, and the solvent was evaporated. The residue was dissolved in 100 ml ether, washed with water 2X and dried over anhydrous MgSO 4 .
  • BA1 prepared according to a literature procedure (Terao, Y; Kotaki, H; Imai, N and Achiwa K. Chemical and Pharmaceutical Bulletin, 33 (7), 1985, 2762-2766) was converted to BA2 using a procedure described by Coldham, I; Crapnell, K.M; Fernandez, J-C; Moseley J. D. and Rabot, R. (Journal of Organic Chemistry, 67 (17), 2002, 6185-6187).
  • BA3 was generated from BA2 using a literature procedure described by Winkler J. D.; Axten J.; Hammach A. H.; Kwak, Y-S; Lengweiler, U.; Lucero, M. J.; Houk, K. N. (Tetrahedron, 54 1998, 7045-7056).
  • Analytical data for compound BA3 MS m/e: 262.1 , 264.1 (M+H).
  • 1 H NMR(CDCI 3 ) 1.43 (s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H).
  • BQ1 was prepared according to Method AZ.
  • NBS N-bromosuccinimide
  • Method CB The following compounds were synthesized using methods similar to Method E and/or AX.
  • Compound CC6 was generated from CC5 using a similar procedure in Method E. Crude compound CC6 was purified by flash chromatography (gradient 0-10% EtOAc in hexane). Two isomers were isolated during purification isomer A which eluted first followed by isomer B.
  • ISOMER A 1 H-NMR (CDCI 3 ) ⁇ 7.26-7.37, m, 5H; 5.57, s, 1H; 5.38, s, 1H; 5.02, q, 2H; 4.08, br s, 1 H; 3.67, s, 3H; 3.08, d, 1 H; 2.58, d, 1 H; 1.80-1.92, m, 1 H; 1.60-1.75, m, 3H; 1.32-1.44, m, 3H; 0.83, s, 9H; 0.35-0.45, m, 4H; 0.01 , s, 6H.
  • ISOMER B 1 H-NMR (CDCI 3 ) ⁇ 7.286-7.36, m, 5H; 5.56, s, 1H; 5.39, s, 1H; 5.06, q, 2H; 4.15, br s, 1H; 3.71 , s, 3H; 3.06, d, 1H; 2.70, d, 1 H, 1.60-1.90, m, 4H; 1.33-1.48, m, 3H; 0.87, s, 9H; 0.37-0.51 , m, 4H; 0.03, s, 6H. Yield 26% isomer A and 22% isomer B.
  • Step 1 terf-Butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate
  • Step 2 te/t-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate
  • Step 4 4-(3-(3,4-Difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine
  • Compound CK3 was obtained from CK2 using method BK, step 3.
  • CK3 (1.18 g, 2.83 mmol) in THF (15 ml_) and 2 N LiOH (4 mL, 8 mmol) was stirred overnight at RT. The mixture was quenched with 6 N HCI (2 mL, 12 mmol) and then partitioned between water and EtOAc. The dried EtOAc layer was concentrated in vacuo and the residue subjected to reverse-phase HPLC (gradient from 10% ⁇ 95% CH 3 CN/H 2 O with 0.1 % HCO 2 H, 30 mL/min flow rate on a preparative C18 reverse-phase column) to afford CK4.
  • reverse-phase HPLC gradient from 10% ⁇ 95% CH 3 CN/H 2 O with 0.1 % HCO 2 H, 30 mL/min flow rate on a preparative C18 reverse-phase column
  • CL2 was obtained from CL1 (3-chlorophenyl boronic acid) following method AW. Method CL, Step 2;
  • Trimethylsilyldiazomethane (2 M hexanes, 2.5 mL, 5.0 mmol) was added to a solution of LDA (freshly prepared from DIPA and "BuLi) in THF at -78° C. After 30 min at -78° C, a solution of aldehyde CL2 (900 mg, 4.13 mmol) in THF (5 mL) was added and the reaction slowly warmed to RT over 3 h. The reaction was quenched with water, then extracted with Et 2 O (2x 100 mL). The combined organic layers were washed with brine (1x), dried over MgSO 4 , filtered, and evaporated under vacuum.
  • LDA freshly prepared from DIPA and "BuLi
  • methanol 20 ml_
  • 10% Pd/C 200 mg
  • the mixture was hydrogenated by a hydrogen balloon for 3 hour 40 min at stirring.
  • the tube was sealed, and evacuated and back-filled with N 2 (5X). The mixture was then exposed to microwave irradiation (110 0 C, 30 min). The resulting mixture was filtered with copious MeOH washes.
  • step 3 CP4 is used to prepare the title compound (CP5).
  • methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl [1-amino-1-(4-chloro)phenyl]ethylphosphonate (CQ1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provides the title compound.
  • step 3 CR3 is used to prepare the title compound.
  • methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl [1-(4-methoxy)phenylmethylamino-2-(4-bromo)phenyl]ethylphosphonate (CS1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provide the title compound.
  • step 3 CS2 is used to prepare the title compound.
  • step 3 is used to prepare the title compound.
  • methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl (2-amino-1-phenyl)ethylphosphonate (CU1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provides the title compound.
  • step 3 CU2 is used to prepare the title compound.
  • step 3 Using a route similar to that described in Method A, step 3, CV3 is used to prepare the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Virology (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Electroluminescent Light Sources (AREA)
  • Gas Separation By Absorption (AREA)

Abstract

L'invention concerne des composés de la formule (I) ou un stéréo-isomère, un tautomère ou un sel ou solvat pharmaceutiquement acceptable de ceux-ci, dans laquelle W est une liaison, -C(=S)-, -S(O)-, -S(O)2-, -C(=O)-, -O-, -C(R6)(R7)-, -N(R5)- ou -C(=N(R5))- ; X est -O-, -N(R5)- ou -C(R6)(R7)- ; pour autant que lorsque X est -O-, U n'est pas -O-, -S(O)-, -S(O)2-, -C(=O)- ou -C(=NR5)- ; U est une liaison, -S(O)-, -S(O)2-, -C(O)-, -O-, -P(O)(OR15)-, -C(=NR5)-, -(C(R6)(R7))b- ou -N(R5)- ; où b est 1 ou 2 ; pour autant que lorsque W est -S(O)-, -S(O)2-, -O-, ou -N(R5)-, U n'est pas -S(O)-, -S(O)2-, -O-, ou -N(R5)- ; pour autant que lorsque X est N(R5)- et W est -S(O)-, -S(O)2-, -O-, ou -N(R5)-, alors U n'est pas une liaison ; et R1, R2, R3, R4, R5, R6, et R7 sont tels que définis dans la description ; et des compositions pharmaceutiques comprenant les composés de la formule (I). Le procédé d'inhibition de la protéase d'aspartyle est également décrit, et en particulier les procédés pour traiter des maladies cardiovasculaires, des maladies cognitives et neurodégénératives ainsi que les procédés d'inhibition du virus d'immunodéficience humaine, de plasmepsines, de cathepsine D et d'enzymes protozoaires. Des procédés pour traiter des maladies cognitives ou neurodégénératives sont également décrits, utilisant les composés de la formule I en combinaison avec un inhibiteur de cholinestérase ou un agoniste muscarinique M1 ou un antagoniste de M2.
PCT/US2008/002182 2007-02-23 2008-02-20 Inhibiteurs de la protéase d'aspartyle hétérocycliques WO2008103351A2 (fr)

Priority Applications (20)

Application Number Priority Date Filing Date Title
JP2009550601A JP5340177B2 (ja) 2007-02-23 2008-02-20 複素環式アスパルチルプロテアーゼ阻害剤
HRP20160876TT HRP20160876T1 (hr) 2007-02-23 2008-02-20 Heterociklični inhibitori aspartil proteaze
DK08714220.4T DK2097387T3 (en) 2007-02-23 2008-02-20 HETEROCYCLIC ASPARTYL PROTEASE INHIBITORS
SI200831653A SI2097387T1 (sl) 2007-02-23 2008-02-20 Heterociklični aspartil proteazni inhibitorji
MX2009009063A MX2009009063A (es) 2007-02-23 2008-02-20 Inhibidores heterociclicos de la aspartil proteasa.
ES08714220.4T ES2582367T3 (es) 2007-02-23 2008-02-20 Inhibidores heterocíclicos de la aspartil proteasa
AU2008219071A AU2008219071B2 (en) 2007-02-23 2008-02-20 Heterocyclic aspartyl protease inhibitors
CA2678958A CA2678958C (fr) 2007-02-23 2008-02-20 Inhibiteurs de la protease d'aspartyle heterocycliques
NZ579301A NZ579301A (en) 2007-02-23 2008-02-20 2-Imino-3,6-dimethyl-5,6-diphenyl-tetrahydropyrimidin-4-one derivatives for treatment of Alzheimer's disease
CN200880013100.0A CN101715442B (zh) 2007-02-23 2008-02-20 杂环天冬氨酰蛋白酶抑制剂
HK09108902.1A HK1130792B (en) 2007-02-23 2008-02-20 Heterocyclic aspartyl protease inhibitors
RU2009135277/04A RU2496774C2 (ru) 2007-02-23 2008-02-20 Гетероциклические ингибиторы аспартильной протеазы
MEP-2016-142A ME02528B (fr) 2007-02-23 2008-02-20 Inhibiteurs de la protéase d'aspartyle hétérocycliques
LTEP08714220.4T LT2097387T (lt) 2007-02-23 2008-02-20 Heterocikliniai aspartilproteazės inhibitoriai
EP08714220.4A EP2097387B1 (fr) 2007-02-23 2008-02-20 Inhibiteurs de la protéase d'aspartyle hétérocycliques
BRPI0807547-6A2A BRPI0807547A2 (pt) 2007-02-23 2008-02-20 Inibidores de aspartil protease hetercíclicos
RS20160558A RS54979B1 (sr) 2007-02-23 2008-02-20 Heterociklični inhibitori aspartil proteaze
ZA2009/05837A ZA200905837B (en) 2007-02-23 2009-08-21 Heterocyclic aspartyl protease inhibitors
IL200561A IL200561A (en) 2007-02-23 2009-08-23 Heterocyclic inhibitors of aspartate protease or their tautomers, their acceptable pharmacy salt, their pharmacy composition and their use
CY20161100753T CY1117946T1 (el) 2007-02-23 2016-07-29 Ετεροκυκλικοι αναστολεις ασπαραγινυλο πρωτεασης

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/710,582 2007-02-23
US11/710,582 US7763609B2 (en) 2003-12-15 2007-02-23 Heterocyclic aspartyl protease inhibitors

Publications (2)

Publication Number Publication Date
WO2008103351A2 true WO2008103351A2 (fr) 2008-08-28
WO2008103351A3 WO2008103351A3 (fr) 2009-07-23

Family

ID=39511364

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/002182 WO2008103351A2 (fr) 2007-02-23 2008-02-20 Inhibiteurs de la protéase d'aspartyle hétérocycliques

Country Status (33)

Country Link
US (5) US7763609B2 (fr)
EP (1) EP2097387B1 (fr)
JP (2) JP5340177B2 (fr)
KR (1) KR101612961B1 (fr)
CN (1) CN101715442B (fr)
AR (2) AR065421A1 (fr)
AU (1) AU2008219071B2 (fr)
BR (1) BRPI0807547A2 (fr)
CA (1) CA2678958C (fr)
CL (1) CL2008000531A1 (fr)
CO (1) CO6220968A2 (fr)
CY (1) CY1117946T1 (fr)
DK (1) DK2097387T3 (fr)
EC (1) ECSP099597A (fr)
ES (1) ES2582367T3 (fr)
HR (1) HRP20160876T1 (fr)
HU (1) HUE029867T2 (fr)
IL (1) IL200561A (fr)
LT (1) LT2097387T (fr)
ME (1) ME02528B (fr)
MX (1) MX2009009063A (fr)
MY (1) MY149183A (fr)
NZ (1) NZ579301A (fr)
PE (2) PE20100731A1 (fr)
PL (1) PL2097387T3 (fr)
PT (1) PT2097387T (fr)
RS (1) RS54979B1 (fr)
RU (1) RU2496774C2 (fr)
SG (1) SG179407A1 (fr)
SI (1) SI2097387T1 (fr)
TW (2) TWI355937B (fr)
WO (1) WO2008103351A2 (fr)
ZA (1) ZA200905837B (fr)

Cited By (84)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7592348B2 (en) 2003-12-15 2009-09-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2009151098A1 (fr) 2008-06-13 2009-12-17 塩野義製薬株式会社 DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DU SOUFRE AYANT UNE ACTIVITÉ INHIBANT LA β-SÉCRÉTASE
US7700603B2 (en) 2003-12-15 2010-04-20 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2010105179A2 (fr) 2009-03-13 2010-09-16 Vitae Pharmaceuticals, Inc. Inhibiteurs de bêta-sécrétase
US7868000B2 (en) 2005-06-14 2011-01-11 Schering Corporation Aspartyl protease inhibitors
WO2010006713A3 (fr) * 2008-07-17 2011-04-14 Bayer Cropscience Ag Composés hétérocycliques utilisés comme pesticides
WO2011044185A2 (fr) 2009-10-08 2011-04-14 Schering Corporation Composés hétérocycliques iminopentafluorosoufrés en tant qu'inhibiteurs de bace-1, compositions et leur utilisation
WO2011044187A1 (fr) 2009-10-08 2011-04-14 Schering Corporation Composés de type dioxyde d'imino-thiadiazine utilisés en tant qu'inhibiteurs de bace, compositions en contenant et leur utilisation
WO2011044181A1 (fr) 2009-10-08 2011-04-14 Schering Corporation Composés de dioxyde d'iminothiadiazine comme inhibiteurs de bace, compositions et leur utilisation
WO2011071135A1 (fr) 2009-12-11 2011-06-16 塩野義製薬株式会社 Dérivé d'oxazine
WO2011115928A1 (fr) 2010-03-15 2011-09-22 Amgen Inc. Composés spiro de l'amino-dihydrooxazine et de l'amino-dihydrothiazine en tant que modulateurs de la béta-sécrétase et utilisation médicale associée
WO2011115938A1 (fr) 2010-03-15 2011-09-22 Amgen Inc. Composés spiro tétracycliques en tant que modulateurs de la béta-sécrétase
US20110275608A1 (en) * 2009-01-12 2011-11-10 Array Biopharma Inc. Piperidine-containing compounds and use thereof
WO2012019056A1 (fr) 2010-08-05 2012-02-09 Amgen Inc. Composés d'amino-iso-indole, d'amino-aza-iso-indole, d'amino-dihydro-isoquinoléine et d'amino-benzoxazine en tant que modulateurs de la bêta-sécrétase et leurs méthodes d'utilisation
US8168630B2 (en) 2007-04-24 2012-05-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8168641B2 (en) 2006-06-12 2012-05-01 Schering Corporation Aspartyl protease inhibitors
US8173642B2 (en) 2005-10-25 2012-05-08 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2012071279A1 (fr) 2010-11-23 2012-05-31 Amgen Inc. Spiro-amino-imidazolones et spiro-amino-dihydro-pyrimidinones en tant que modulateurs de bêta-sécrétase et leurs méthodes d'utilisation
WO2012109165A1 (fr) 2011-02-07 2012-08-16 Amgen Inc. Composés de 5-amino-oxazépine et 5-amino-thiazépane en tant qu'antagonistes de la bêta-sécrétase et leurs procédés d'utilisation
WO2012112462A1 (fr) 2011-02-15 2012-08-23 Amgen Inc. Composés hétérocycliques spiro-amino-imidazo-condensés en tant que modulateurs de la bêta-secrétase et méthodes d'utilisation
WO2012138734A1 (fr) 2011-04-07 2012-10-11 Merck Sharp & Dohme Corp. Composés de dioxyde de thiadiazine condensés avec des dérivés oxacycliques en c5-c6 comme inhibiteurs de bace, compositions, et utilisation use
WO2013028670A1 (fr) 2011-08-22 2013-02-28 Merck Sharp & Dohme Corp. Iminothiazines 2-spiro-substituées et leur mono- et dioxydes en tant qu'inhibiteurs bace, compositions et leur utilisation
WO2013044092A1 (fr) 2011-09-21 2013-03-28 Amgen Inc. Composés d'amino-oxazines et d'amino-dihydrothiazine comme modulateurs de sécrétase bêta et procédés d'utilisation
US8426447B2 (en) 2008-09-11 2013-04-23 Amgen Inc. Spiro-tricyclic ring compounds as beta-secretase modulators and methods of use
US8450308B2 (en) 2008-08-19 2013-05-28 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8450331B2 (en) 2008-04-22 2013-05-28 Merck Sharp & Dohme Corp. Thiophenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
WO2014062553A1 (fr) 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Composés de dioxyde de thiadiazine substituée tricyclique utilisés en tant qu'inhibiteurs de bace, compositions et leur utilisation
WO2014062549A1 (fr) 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Composés de dioxyde de thiadiazine substitués tricycliques en tant qu'inhibiteurs de bace, compositions et leur utilisation
US8722708B2 (en) 2005-06-14 2014-05-13 Merck Sharp & Dohme Inc. Substituted isoindolines as aspartyl protease inhibitors
WO2014078314A1 (fr) 2012-11-15 2014-05-22 Amgen Inc. Composés d'amino-oxazine et d'amino-dihydrothiazine jouant le rôle de modulateurs de bêta-sécrétase et procédés d'utilisation
WO2014127881A1 (fr) 2013-02-25 2014-08-28 Merck Patent Gmbh Dérivés de 2-amino-3,4-dihydroquinazoline et leur utilisation comme inhibiteurs de la cathepsine d
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
US8981112B2 (en) 2012-03-05 2015-03-17 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9018391B2 (en) 2012-08-27 2015-04-28 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9353089B2 (en) 2013-03-26 2016-05-31 Saint Louis University Compositions and methods for the treatment of malaria
US9365589B2 (en) 2012-12-20 2016-06-14 Merck Sharp & Dohme Corp. C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9447085B2 (en) 2012-12-14 2016-09-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxides containing a thioamide, amidine, or amide oxime group as BACE inhibitors, compositions, and their use
WO2016172255A1 (fr) * 2015-04-21 2016-10-27 Allgenesis Biotherapeutics, Inc. Composés et leur utilisation en tant qu'inhibiteurs de bace1
US9489013B2 (en) 2012-12-20 2016-11-08 Merck Sharp & Dohme Corp. C6-azaspiro iminothiadiazine dioxides as bace inhibitors, compositions, and their use
US9499502B2 (en) 2011-04-13 2016-11-22 Merck Sharp & Dohme Corp. 5-substituted iminothiazines and their mono- and dioxides as BACE inhibitors, compositions, and their use
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9580396B2 (en) 2012-12-21 2017-02-28 Merck Sharp & Dohme Corp. C6-spiro iminothiadiazine dioxides as BACE inhibitors, compositions, and their use
US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2017061534A1 (fr) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dérivés de dihydrothiazine
WO2017089453A1 (fr) 2015-11-25 2017-06-01 Ucb Biopharma Sprl Dérivés d'iminotétrahydropyrimidinone utilisés comme inhibiteurs de plasmepsine v
CN106810458A (zh) * 2016-12-31 2017-06-09 武汉工程大学 一种拆分dl‑2‑氨基丙醇制备l‑2‑氨基丙醇的方法
US9725468B2 (en) 2013-09-13 2017-08-08 Merck Sharp & Dohme Corp. C5-spiro iminothiazine dioxides as BACE inhibitors, compositions, and their use
US9745324B2 (en) 2013-12-18 2017-08-29 Merck Sharp & Dohme Corp. Iminothiadiazepane dioxide compounds as BACE inhibitors, compositions, and their use
WO2017144517A1 (fr) 2016-02-23 2017-08-31 Ucb Biopharma Sprl Dérivés de dioxyde d'iminothiadiazinane utilisés comme inhibiteurs de la plasmepsine v
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9802928B2 (en) 2013-12-18 2017-10-31 Merck Sharp & Dohme Corp. C-6 spirocarbocyclic iminothiadiazine dioxides as BACE inhibitors, compositions, and their use
WO2018033455A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2018106519A1 (fr) * 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques en tant qu'inhibiteurs de la protéase du vih
WO2018118827A1 (fr) * 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Composés hétérocycliques utiles en tant qu'inhibiteurs de la protéase du vih
WO2018118829A1 (fr) * 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Composés hétérocycliques en tant qu'inhibiteurs de la protéase du vih
US10238643B2 (en) 2009-07-22 2019-03-26 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10265311B2 (en) 2009-07-22 2019-04-23 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
WO2019192992A1 (fr) 2018-04-06 2019-10-10 Ucb Biopharma Sprl Analogues d'hexahydropyrimidine antipaludiques
EP3416645A4 (fr) * 2016-02-18 2019-10-16 Merck Sharp & Dohme Corp. Composés pour le traitement du paludisme
EP3416647A4 (fr) * 2016-02-18 2019-10-23 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
EP3607946A1 (fr) 2012-03-19 2020-02-12 Buck Institute for Research on Aging Inhibiteurs de bace spécifiques app (asbis) et leurs utilisations
EP3653609A1 (fr) 2013-02-12 2020-05-20 Buck Institute for Research on Aging Hydantoïnes modulant le traitement de précurseur du peptide amyloïde (app) à médiation par bêta-secrétase (bace)
KR20200071098A (ko) * 2017-10-13 2020-06-18 길리애드 사이언시즈, 인코포레이티드 Hiv 프로테아제 억제제로서의 1-벤질-2-이미노-4-페닐-5-옥소이미다졸리딘 유도체
WO2020214716A1 (fr) * 2019-04-17 2020-10-22 Gilead Sciences, Inc. Inhibiteurs de la protéase du vih à base de 2-imino-5-oxo-imidazolidine
WO2020229427A1 (fr) 2019-05-14 2020-11-19 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques
WO2021027502A1 (fr) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Agents antipaludiques
US10925832B2 (en) 2018-09-28 2021-02-23 Karuna Therapeutics, Inc. Compositions and methods for treatment of disorders ameliorated by muscarinic receptor activation
WO2021032687A1 (fr) 2019-08-19 2021-02-25 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques
WO2021101836A1 (fr) * 2019-11-19 2021-05-27 Merck Sharp & Dohme Corp. Agents antipaludiques
WO2021155791A1 (fr) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Agents antipaludiques
WO2022008639A1 (fr) 2020-07-10 2022-01-13 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity
WO2023102747A1 (fr) * 2021-12-07 2023-06-15 Merck Sharp & Dohme Llc Agents antipaludiques
WO2023152042A1 (fr) 2022-02-08 2023-08-17 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3259012B2 (ja) 1995-08-02 2002-02-18 ミヤチテクノス株式会社 インバータ式抵抗溶接制御装置
JP3259013B2 (ja) 1995-08-10 2002-02-18 ミヤチテクノス株式会社 インバータ式抵抗溶接電源装置
EP1896477B1 (fr) * 2005-06-14 2010-09-22 Schering Corporation Inhibiteurs de l'aspartyl protease
EP2194047A1 (fr) * 2005-06-14 2010-06-09 Schering Corporation Préparation et utilisation d'inhibiteurs d'aspartyl protease
BRPI0620025A2 (pt) * 2005-12-19 2011-10-25 Wyeth Corp composto, método para o tratamento de uma doença ou transtorno associado a atividade excessiva de bace, método para modular a atividade de bace, composição farmacêutica e uso do composto
US20100016341A1 (en) * 2006-12-12 2010-01-21 Zhaoning Zhu Aspartyl protease inhibitors containing a tricyclic ring system
KR20090087487A (ko) 2006-12-12 2009-08-17 쉐링 코포레이션 아스파르틸 프로테아제 억제제
DE102008063992A1 (de) * 2008-12-19 2010-09-02 Lerner, Zinoviy, Dipl.-Ing. Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung
GB0912777D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydropyrimidone derivatives
GB0912778D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydro-oxazine derivatives
GB201100181D0 (en) 2011-01-06 2011-02-23 Eisai Ltd Fused aminodihydrothiazine derivatives
GB201101139D0 (en) 2011-01-21 2011-03-09 Eisai Ltd Fused aminodihydrothiazine derivatives
GB201101140D0 (en) 2011-01-21 2011-03-09 Eisai Ltd Fused aminodihydrothiazine derivatives
EP2703399A4 (fr) 2011-04-26 2014-10-15 Shionogi & Co Dérivé d'oxazine et inhibiteur de bace 1 le contenant
WO2013142396A1 (fr) * 2012-03-23 2013-09-26 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées en n3 en tant qu'inhibiteurs de la rénine, compositions et leur utilisation
EP2669286A1 (fr) * 2012-05-31 2013-12-04 Ares Trading S.A. Dérivés de spiro tétrahydro-benzothiophène utiles pour le traitement de maladies neuro-dégénératives
US9353072B2 (en) * 2012-10-31 2016-05-31 Purdue Research Foundation Antimicrobial substituted thiazoles and methods of use
WO2016040226A1 (fr) 2014-09-12 2016-03-17 Merck Sharp & Dohme Corp. Composés de s-imino-s-oxo iminothiazine en tant qu'inhibiteurs de bace, compositions, et leur utilisation
US9868738B2 (en) 2014-09-19 2018-01-16 Merck Sharp & Dohme Corp. Diazine-fused amidines as BACE inhibitors, compositions, and their use
US10047098B2 (en) 2014-11-25 2018-08-14 Merck Sharp & Dohme Corp. C5-C6-oxacyclic fused iminopyrimidinone compounds as bace inhibitors, compositions, and their use
EP3261442B1 (fr) 2015-01-20 2020-04-01 Merck Sharp & Dohme Corp. Dioxydes d'iminothiadiazine portant un substituant lié à une amine, utilisés en tant qu'inhibiteurs de bace, compositions les contenant et leur utilisation
WO2017095759A1 (fr) 2015-12-04 2017-06-08 Merck Sharp & Dohme Corp. Dioxydes d'iminothiadiazine carboxyliques en c5-c6 condensés utilisés comme inhibiteurs de bace, compositions, et utilisation associée
US10689401B2 (en) 2016-02-11 2020-06-23 Merck Sharp & Dohme Corp. C5-C6-oxacyclic fused iminothiazine dioxide compounds bearing an ether linker as BACE inhibitors, compositions, and their use
WO2017139210A1 (fr) 2016-02-11 2017-08-17 Merck Sharp & Dohme Corp. Composés de dioxyde d'iminothiadiazine condensé oxacyclique en c5-c6 portant un coupleur de type éther utilisés en tant qu'inhibiteurs de bace, compositions, et leur utilisation
EP3428150B1 (fr) * 2016-03-11 2023-07-12 Takeda Pharmaceutical Company Limited Composé cyclique aromatique ayant une activité modulatrice allostérique positive sur le récepteur cholinergique de la muscarine m1
US11352328B2 (en) 2016-07-12 2022-06-07 Arisan Therapeutics Inc. Heterocyclic compounds for the treatment of arenavirus
CN109641884B (zh) 2016-08-18 2024-01-02 维达克制药有限公司 哌嗪衍生物、其药物组合物及其使用方法
US10844044B2 (en) * 2018-06-14 2020-11-24 Vanderbilt University WDR5 inhibitors and modulators
US12419865B2 (en) 2018-12-06 2025-09-23 Arisan Therapeutics Inc. Compounds for the treatment of arenavirus infection
CN110066221B (zh) * 2019-05-16 2022-03-08 海门瑞一医药科技有限公司 一种环丙基甲胺的制备方法
CN110256285B (zh) * 2019-07-09 2022-03-18 上海出入境检验检疫局动植物与食品检验检疫技术中心 一种稳定同位素标记拟除虫菊酯的合成方法

Family Cites Families (274)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3200123A (en) 1962-01-26 1965-08-10 Richardson Merreil Inc Imidazoquinolines
US3197476A (en) 1962-12-06 1965-07-27 Air Prod & Chem Method of synthesis of 1-acyl imidazoles
US3632814A (en) 1968-11-25 1972-01-04 Velsicol Chemical Corp Phosphoramidate esters
ZA87563B (en) 1986-02-03 1987-09-30 Squibb & Sons Inc N-heterocyclic alcohol renin inhibitors
DE3643890A1 (de) 1986-12-22 1988-06-30 Basf Ag Neue polyalkylpiperidinderivate mit alkylenbruecken, ihre verwendung als stabilisator und zwischenprodukte
JPH03500772A (ja) 1987-10-21 1991-02-21 ジ・アップジョン・カンパニー （１‐アミノ‐２‐ヒドロキシ‐２‐ヘテロサイクリック）エチル基を含有するレニン抑制物質類
EP0361341A3 (fr) 1988-09-28 1991-07-03 Miles Inc. Agents thérapeutiques contre le SIDA basés sur des inhibiteurs des protéases du HIV
IL92011A0 (en) 1988-10-19 1990-07-12 Abbott Lab Heterocyclic peptide renin inhibitors
US5852029A (en) * 1990-04-10 1998-12-22 Israel Institute For Biological Research Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity
US5534520A (en) 1990-04-10 1996-07-09 Fisher; Abraham Spiro compounds containing five-membered rings
GB9109972D0 (en) 1991-05-09 1991-07-03 Ici Plc Therapeutic compounds
US5731431A (en) * 1991-12-26 1998-03-24 Nippon Soda Co., Ltd. Process for preparing 4-substituted azetidinone derivatives
ES2157214T3 (es) 1991-12-26 2001-08-16 Nippon Soda Co Procedimiento para producir derivados de azetidinona sustituidos en posicion 4.
ES2148229T3 (es) 1992-05-20 2000-10-16 Merck & Co Inc Eteres y tioeteres en la posicion 17 de 4-aza-esteroides.
US5610162A (en) 1992-05-20 1997-03-11 Merck & Co., Inc. Ester derivatives of 4-aza-steroids
DE4233715A1 (de) * 1992-10-07 1994-04-14 Bayer Ag Substituierte Carbamoylpyrazoline
US5338740A (en) * 1993-07-13 1994-08-16 Pfizer Inc. Angiotensin II receptor antagonists
US5502222A (en) 1994-06-01 1996-03-26 Schering Corporation Process for preparing delta 9,11 and 21-chloro corticosteroids
IL117149A0 (en) * 1995-02-23 1996-06-18 Schering Corp Muscarinic antagonists
US5889006A (en) * 1995-02-23 1999-03-30 Schering Corporation Muscarinic antagonists
US5691372A (en) * 1995-04-19 1997-11-25 Vertex Pharmaceuticals Incorporated Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease
JPH11509846A (ja) 1995-07-31 1999-08-31 ノボ ノルディスク アクティーゼルスカブ ヘテロ環式化合物、それらの調製及び使用
FR2741342B1 (fr) 1995-11-22 1998-02-06 Roussel Uclaf Nouvelles phenylimidazolidines fluorees ou hydroxylees, procede, intermediaires de preparation, application comme medicaments, nouvelle utilisation et compositions pharmaceutiques
GB9611046D0 (en) 1996-05-25 1996-07-31 Wivenhoe Techn Ltd Pharmacological compounds
US5935958A (en) * 1996-07-01 1999-08-10 Schering Corporation Muscarinic antagonists
US5952349A (en) * 1996-07-10 1999-09-14 Schering Corporation Muscarinic antagonists for treating memory loss
GB9615831D0 (en) 1996-07-27 1996-09-11 Agrevo Uk Ltd Fungicides
US5977138A (en) * 1996-08-15 1999-11-02 Schering Corporation Ether muscarinic antagonists
US5981556A (en) 1997-07-22 1999-11-09 G.D. Searle & Co. 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors
JPH11335518A (ja) 1998-03-25 1999-12-07 Polyplastics Co ポリアセタ―ル樹脂組成物およびその製造方法
US6066636A (en) * 1998-06-30 2000-05-23 Schering Corporation Muscarinic antagonists
US6638937B2 (en) 1998-07-06 2003-10-28 Bristol-Myers Squibb Co. Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
US6413725B1 (en) * 1998-08-07 2002-07-02 California Institute Of Technology Biochemical assay to monitor the ubiquitin ligase activities of cullins
US6864240B1 (en) 1999-06-15 2005-03-08 Elan Pharmaceuticals, Inc. Dipeptide inhibitors of β-secretase
AU5771500A (en) 1999-06-28 2001-01-31 Oklahoma Medical Research Foundation Catalytically active recombinant memapsin and methods of use thereof
US6492408B1 (en) 1999-07-21 2002-12-10 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
US6294554B1 (en) * 1999-09-22 2001-09-25 Schering Corporation Muscarinic antagonists
ATE339417T1 (de) 1999-12-15 2006-10-15 Bristol Myers Squibb Co Biphenyl - sulfonamide als duale angiotensin - endothelin - rezeptor - antagonisten
DE60124080T2 (de) 2000-03-23 2007-03-01 Elan Pharmaceuticals, Inc., San Francisco Verbindungen und verfahren zur behandlung der alzheimerschen krankheit
JP2003535046A (ja) 2000-04-03 2003-11-25 デュポン ファーマシューティカルズ カンパニー Ａβタンパク質産生の阻害剤としての環状ラクタム
EP1289966A1 (fr) 2000-04-11 2003-03-12 Bristol-Myers Squibb Pharma Company LACTAMES SUBSTITUES UTILISES EN TANT QU'INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b)
US6713276B2 (en) 2000-06-28 2004-03-30 Scios, Inc. Modulation of Aβ levels by β-secretase BACE2
US6846813B2 (en) 2000-06-30 2005-01-25 Pharmacia & Upjohn Company Compounds to treat alzheimer's disease
ATE314343T1 (de) 2000-06-30 2006-01-15 Elan Pharm Inc Verbindungen zur behandlung der alzheimerischen krankheit
PE20020276A1 (es) 2000-06-30 2002-04-06 Elan Pharm Inc COMPUESTOS DE AMINA SUSTITUIDA COMO INHIBIDORES DE ß-SECRETASA PARA EL TRATAMIENTO DE ALZHEIMER
AU2001273429A1 (en) 2000-07-14 2002-01-30 Vigilant Networks Llc Single ended attenuation measurement
US6344473B1 (en) * 2000-08-07 2002-02-05 G.D. Searle & Co. Imidazoles useful as nitric oxide synthase inhibitors
US6414161B1 (en) 2000-08-09 2002-07-02 Boehringer Ingelheim Pharmaceuticals, Inc. Synthesis of (R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-a]imidazol-2-one
AR035612A1 (es) * 2000-12-22 2004-06-16 Schering Corp 4-(piperidin-4-ilmetil)benzamidas, o sus sales, esteres o solvatos, composiciones farmaceuticas que los comprenden, usos de los mismos para preparar medicamentos, y un kit para utilizar en el tratamiento de una enfermedad cognitiva o neurodegenerativa
WO2002062803A1 (fr) 2001-02-08 2002-08-15 Yamanouchi Pharmaceutical Co., Ltd. Derive de thienopyrimidine
AU2002306734A1 (en) 2001-03-15 2002-10-03 The Johns Hopkins University Inhibitors of plasmepsins
EP1389194A2 (fr) 2001-04-27 2004-02-18 Vertex Pharmaceuticals Incorporated Inhibiteurs de bace
US7384773B1 (en) 2001-05-10 2008-06-10 Pfizer Inc Crystal of HIV protease-cleaved human beta secretase and method for crystallization thereof
US7144897B2 (en) 2001-06-01 2006-12-05 Elan Oharmaceuticals, Inc. Hydroxy alkyl amines
US20070213407A1 (en) 2001-06-29 2007-09-13 Elan Pharmaceuticals And Pharmacia & Upjohn Company Llc Compounds to treat Alzheimer's disease
MXPA04003245A (es) 2001-10-04 2004-08-11 Elan Pharm Inc Hidroxipropilaminas.
CA2462861A1 (fr) 2001-10-10 2003-04-17 Yuguang Wang Composes de piperidine servant d'antagonistes muscariniques
US6673821B2 (en) 2001-10-22 2004-01-06 Enanta Pharmaceuticals, Inc. Nitrogen heterocycle inhibitors of aspartyl protease
AU2002359301B2 (en) 2001-10-23 2008-07-03 Comentis, Inc. Beta-secretase inhibitors and methods of use
TW200304808A (en) 2001-11-08 2003-10-16 Elan Pharm Inc N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives
BR0214295A (pt) 2001-11-19 2004-11-09 Elan Pharm Inc Composto, método para tratar um paciente que tem ou prevenir um paciente de adquirir uma doença ou condição, e, método para produzir um composto
JP2005511735A (ja) 2001-12-06 2005-04-28 イーラン ファーマスーティカルズ、インコーポレイテッド 置換ヒドロキシエチルアミン
CN1289469C (zh) 2001-12-20 2006-12-13 布里斯托尔-迈尔斯斯奎布公司 α－(N－磺酰氨基)乙酰胺衍生物作为β－淀粉样蛋白抑制剂
CA2477243A1 (fr) 2002-02-21 2003-09-04 Pharmacia & Upjohn Company Enzyme bace modifiee
US7132568B2 (en) 2002-06-17 2006-11-07 Sunesis Pharmaceuticals, Inc. Aspartyl protease inhibitors
US7459476B2 (en) 2002-06-27 2008-12-02 Elan Pharmaceuticals, Inc. Methods for treating Alzheimer's disease using hydroxyethylene compounds containing a heterocyclic amide bond isostere
WO2004022523A2 (fr) 2002-09-06 2004-03-18 Elan Pharmaceuticals, Inc. Derives de promedicaments a base de 1, 3-diamino-2-hydroxypropane
UY27967A1 (es) 2002-09-10 2004-05-31 Pfizer Acetil 2-hindroxi-1,3-diaminoalcanos
JP2006504725A (ja) 2002-10-09 2006-02-09 ファイザー・プロダクツ・インク 神経変性障害治療用ピラゾール化合物
WO2004042026A2 (fr) 2002-11-04 2004-05-21 Florida State University Research Foundation Acide nucleique et polypeptides allergenes codes par cet acide nucleique dans des noix de cajou (anacardium occidentale)
WO2004043916A1 (fr) 2002-11-12 2004-05-27 Merck & Co., Inc. Inhibiteurs de beta-secretase phenylcarboxamide utilises dans le traitement de la maladie d'alzheimer
PE20040762A1 (es) 2002-11-27 2004-11-06 Elan Pharm Inc Ureas substituidas y carbamatos utiles para el tratamiento de la enfermedad de alzheimer
GB0228410D0 (en) 2002-12-05 2003-01-08 Glaxo Group Ltd Novel Compounds
AU2003299791A1 (en) 2002-12-20 2004-07-22 Bayer Pharmaceuticals Corporation Substituted 3,5-dihydro-4h-imidazol-4-ones for the treatment of obesity
US7354933B2 (en) * 2003-01-31 2008-04-08 Aventis Pharma Sa Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
FR2850652B1 (fr) 2003-01-31 2008-05-30 Aventis Pharma Sa Nouveaux derives d'uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases
CA2515975C (fr) 2003-02-28 2013-02-05 Yoshiaki Kiso Derives peptidiques a activite inhibitrice de la .beta.-secretase
MXPA05011150A (es) 2003-04-21 2005-12-14 Elan Pharm Inc 2-hidroxi-3-diaminoalcanos de benzamida.
GB0309221D0 (en) 2003-04-23 2003-06-04 Glaxo Group Ltd Novel compounds
WO2004099200A1 (fr) 2003-05-12 2004-11-18 Pfizer Products Inc. Composes isoxazoliques et isothiazoliques destines au traitement de troubles neurodegeneratifs
GB0314302D0 (en) 2003-06-19 2003-07-23 Glaxo Group Ltd Novel compounds
WO2005004802A2 (fr) 2003-06-30 2005-01-20 Merck & Co., Inc. Inhibiteurs de la beta-secretase a base de n-alkyle phenylcarboxamide pour le traitement de la maladie d'alzheimer
DE10336035A1 (de) 2003-08-01 2005-03-24 Endress + Hauser Wetzer Gmbh + Co Kg Verfahren zur automatischen Anpassung eines busfähigen Feldgerätes der Prozessautomatisierungstechnik an das auf dem Feldbus verwendete Busprotokoll
JP4472700B2 (ja) 2003-08-08 2010-06-02 シェーリング コーポレイション 複素環置換基を有する環状アミンｂａｓｅ−１阻害剤
DE602004019793D1 (de) 2003-08-08 2009-04-16 Schering Corp Cyclische amine mit benzamidsubstituent als bace-1-inhibitoren
CA2534532A1 (fr) 2003-08-21 2005-03-10 Pfizer Products, Inc. Composes pour le traitement de maladies neurodegeneratives
EP1694635A2 (fr) 2003-10-30 2006-08-30 Elan Pharmaceuticals, Inc. Hydroxypropylamides pour le traitement de la maladie d'alzheimer
US20050171112A1 (en) * 2003-11-03 2005-08-04 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
US20060034848A1 (en) * 2003-11-07 2006-02-16 Ayae Kinoshita Methods and compositions for treating Alzheimer's disease
EP2388637A3 (fr) 2003-11-21 2012-11-14 Visual Physics, LLC Sécurité micro-optique et système de présentation d'images
US7592348B2 (en) * 2003-12-15 2009-09-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7700603B2 (en) 2003-12-15 2010-04-20 Schering Corporation Heterocyclic aspartyl protease inhibitors
EP2153832B1 (fr) 2003-12-15 2016-03-09 Merck Sharp & Dohme Corp. Inhibiteurs de protéase aspartyle hétérocyclique
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2005065195A2 (fr) 2003-12-19 2005-07-21 Merck & Co., Inc. Inhibiteurs de phenylamide et de pyridylamide de la beta-secretase, traitant la maladie d'alzheimer
US7205370B2 (en) * 2004-01-12 2007-04-17 Bridgestone Corporation Polymeric nano-particles of flower-like structure and applications
JP2007522129A (ja) 2004-01-21 2007-08-09 エラン ファーマシューティカルズ，インコーポレイテッド アスパラギン酸プロテアーゼ阻害薬を用いるアミロイドーシスの処置方法
WO2005087215A1 (fr) 2004-03-09 2005-09-22 Elan Pharmaceuticals, Inc. Uree et carbamate substitues, phenacyl-2-hydroxy-3-diaminoalcane, et benzamide-2-hydroxy-3-diaminoalcane inhibiteurs d'aspartyl-protease
AU2005230878A1 (en) 2004-03-30 2005-10-20 Merck & Co., Inc. 2-aminothiazole compounds useful as aspartyl protease inhibitors
US7244757B2 (en) 2004-04-01 2007-07-17 Pfizer Inc Pyrazole-amine compounds for the treatment of neurodegenerative disorders
US7232820B2 (en) 2004-04-01 2007-06-19 Pfizer Inc Thiadiazole-amine compounds for the treatment of neurodegenerative disorders
US7968571B2 (en) 2004-04-20 2011-06-28 Merck, Sharp & Dohme, Corp. 2,4,6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's Disease
CN1942457A (zh) 2004-04-20 2007-04-04 默克公司 作为β－促分泌酶抑制剂用于阿尔茨海默氏病的治疗中的1,3,5－取代的苯基衍生化合物
US7585885B2 (en) 2004-04-22 2009-09-08 Eli Lilly And Company Pyrrolidine derivatives useful as BACE inhibitors
JP2007533741A (ja) 2004-04-22 2007-11-22 イーライ リリー アンド カンパニー Ｂａｃｅ阻害剤
EP1756040A4 (fr) 2004-05-13 2008-04-30 Merck & Co Inc Composés de phényl carboxamide utilisables comme inhibiteurs de bêta sécrétase dans le traitement de la maladie d"alzheimer
WO2005113582A1 (fr) 2004-05-22 2005-12-01 Boehringer Ingelheim International Gmbh Ethane-1,2-diamines substituees pour le traitement de la maladie d'alzheimer
CA2570995A1 (fr) 2004-06-15 2006-01-05 Merck & Co., Inc. Composes pyrrolidin-3-yle utiles en tant qu'inhibiteurs de la beta-secretase pour le traitement de la maladie d'alzheimer
PE20060526A1 (es) 2004-06-15 2006-07-13 Schering Corp Compuestos triciclicos como antagonistas de mglur1
NZ552031A (en) 2004-06-16 2009-06-26 Wyeth Corp Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase
AU2005264917A1 (en) 2004-06-16 2006-01-26 Wyeth Diphenylimidazopyrimidine and -imidazole amines as inhibitors of B-secretase
US7385085B2 (en) 2004-07-09 2008-06-10 Elan Pharmaceuticals, Inc. Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors
US7803802B2 (en) 2004-07-22 2010-09-28 Schering Corporation Substituted amide beta secretase inhibitors
CA2575340A1 (fr) 2004-07-28 2006-02-09 Schering Corporation Inhibiteurs de beta-secretase macrocycliques
DE602005023887D1 (de) 2004-08-06 2010-11-11 Janssen Pharmaceutica Nv Als b-sekretase (bace)-hemmer nützliche 2-amino-chinazolinderivate
EP1776350B1 (fr) 2004-08-06 2013-01-23 Janssen Pharmaceutica NV NOUVEAUX DERIVES DE 2-AMINO-QUINAZOLINE UTILES EN TANT QU'INHIBITEURS DE LA ß-SECRETASE (BACE)
US8436006B2 (en) 2004-08-06 2013-05-07 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
WO2006018287A1 (fr) 2004-08-17 2006-02-23 Novartis Ag Structure tridimensionnelle de l'enzyme de clivage du site beta de la proteine precurseur de l'amyloide de type 2 (bace2) du type aspartyl protease humaine, methodes et utilisation correspondantes
US7388007B2 (en) 2004-08-26 2008-06-17 Bristol-Myers Squibb Company Gamma-lactams as beta-secretase inhibitors
CA2576782A1 (fr) 2004-08-27 2006-03-09 Elan Pharmaceuticals, Inc. Methodes de traitement de l'amylose comprenant l'administration d'inhibiteurs de l'aspartyle protease comprenant une ethanol-amine cyclique substituee
WO2006029850A1 (fr) 2004-09-14 2006-03-23 The Genetics Company, Inc. Derives d'hydrazone et leur utilisation comme inhibiteurs de la beta-secretase
WO2006034277A1 (fr) 2004-09-17 2006-03-30 Comentis, Inc. Composes bicycliques inhibant l'activite de la beta-secretase et procedes d'utilisation associes
PE20060692A1 (es) 2004-09-21 2006-07-19 Lilly Co Eli Inhibidores bace
GB0422766D0 (en) 2004-10-13 2004-11-17 Glaxo Group Ltd Novel compounds
GB0422755D0 (en) 2004-10-13 2004-11-17 Glaxo Group Ltd Novel compounds
CA2583342A1 (fr) 2004-10-13 2006-04-27 Merck And Co., Inc. Composes de spiropiperidine utilises comme inhibiteurs de beta-secretase en vue du traitement de la maladie d'alzheimer
GB0422765D0 (en) 2004-10-13 2004-11-17 Glaxo Group Ltd Novel compounds
EP1802588A4 (fr) 2004-10-15 2010-02-17 Astrazeneca Ab Amino-pyrimidones substitues et utilisation de ceux-ci
US20090221579A1 (en) 2004-10-15 2009-09-03 Jeffrey Scott Albert Substituted Amino-Compounds and Uses Thereof
CA2585279A1 (fr) 2004-10-29 2006-06-08 Merck & Co., Inc. Composes de 2-aminopyridine utiles comme inhibiteurs de la beta-secretase pour le traitement de la maladie d'alzheimer
WO2006050862A1 (fr) 2004-11-10 2006-05-18 Boehringer Ingelheim International Gmbh Dérivés de statine dans le traitement de la maladie d'alzheimer
JP2008520727A (ja) 2004-11-23 2008-06-19 メルク エンド カムパニー インコーポレーテッド アルツハイマー病の治療のための大環状アミノピリジルβ−セクレターゼ阻害剤
ES2259891B1 (es) 2004-11-30 2007-11-01 Laboratorios Almirall S.A. Nuevos derivados de piridotienopirimidina.
CN101115749B (zh) * 2004-12-17 2011-06-22 安姆根有限公司 氨基嘧啶化合物和使用方法
GB0500683D0 (en) 2005-01-13 2005-02-23 Novartis Ag Organic compounds
EP2264036A1 (fr) 2005-01-14 2010-12-22 Wyeth LLC (Formerly Known As Wyeth) Amino-imidazolones destinés à l' inhibition de la beta-secretase
EP1841426B1 (fr) 2005-01-19 2011-04-27 Merck Sharp & Dohme Corp. Carbinamines tertiaires incluant des heterocycles substitues, agissant en tant qu'inhibiteurs de la beta-secretase et utilisees dans le traitement de la maladie d'alzheimer
EP1855679B1 (fr) 2005-01-19 2016-06-29 Merck Sharp & Dohme Corp. Inhibiteurs de la beta-secretase d'aminomethyle dans le traitement de la maladie d'alzheimer
WO2006081072A1 (fr) 2005-01-24 2006-08-03 Abbott Laboratories Antagonistes du recepteur mglu et leurs utilisations
JP2008528573A (ja) 2005-01-27 2008-07-31 アルマ マテル ストゥディオルム−ウニヴェルシタ ディ ボローニャ アルツハイマー病の処置に有用な有機化合物、それらの使用及び調製の方法
US20070299093A1 (en) 2005-01-27 2007-12-27 Alma Mater Studiorum-Universitá Di Bologna Organic Compounds Useful for the Treatment of Alzheimer's Disease, Their Use and Method of Preparation
WO2006083760A1 (fr) 2005-02-01 2006-08-10 Wyeth Aminopyridines constituant des inhibiteurs de la $g(b)-secretase
WO2006088705A1 (fr) 2005-02-14 2006-08-24 Wyeth Guanidine de terphenyle en tant qu'inhibiteurs de la $g(b)-secretase
KR20070102751A (ko) 2005-02-14 2007-10-19 와이어쓰 β-세크레타제 억제제로서의 아졸릴아실구아니딘
WO2006088694A1 (fr) 2005-02-14 2006-08-24 Wyeth THIÉNYL- ET FURYLACYLGUANIDINE SUBSTITUÉES ET MÉTHODES D'EMPLOI DESDITS COMPOSÉS EN TANT QUE RÉGULATEURS DE LA β-SECRÉTASE
US7745470B2 (en) 2005-03-10 2010-06-29 Bristol-Myers Squibb Company Isophthalates as beta-secretase inhibitors
EP1871739A1 (fr) 2005-04-08 2008-01-02 Comentis, Inc. Composes inhibant l'activite beta-secretase et leurs methodes d'utilisation
WO2006133588A1 (fr) 2005-06-13 2006-12-21 Oncalis Ag COMPOSÉS ARYL URÉE COMME INHIBITEURS DE LA β-SECRÉTASE
EP1896477B1 (fr) * 2005-06-14 2010-09-22 Schering Corporation Inhibiteurs de l'aspartyl protease
WO2006138265A2 (fr) 2005-06-14 2006-12-28 Schering Corporation Preparation et utilisation de composes en tant qu'inhibiteurs de proteases
MX2007016186A (es) 2005-06-14 2008-03-07 Schering Corp Preparacion y uso de inhibidores de proteasas.
EP2194047A1 (fr) 2005-06-14 2010-06-09 Schering Corporation Préparation et utilisation d'inhibiteurs d'aspartyl protease
CN101193892A (zh) 2005-06-14 2008-06-04 先灵公司 大环杂环天冬氨酰基蛋白酶抑制剂
TWI332005B (en) 2005-06-14 2010-10-21 Schering Corp Aspartyl protease inhibitors
JP2008543844A (ja) 2005-06-14 2008-12-04 シェーリング コーポレイション アスパルチルプロテアーゼ阻害剤
AU2006262381A1 (en) 2005-06-21 2007-01-04 Medimmune, Llc Methods and compositions for expressing negative-sense viral RNA in canine cells
WO2007002220A2 (fr) 2005-06-21 2007-01-04 Bristol-Myers Squibb Company Guanidines d'acyle acetamide amine en tant qu'inhibiteurs de beta-secretase
WO2007002214A2 (fr) 2005-06-21 2007-01-04 Bristol-Myers Squibb Company Acylguanidines en tant qu'inhibiteur de beta-secretase
TW200738683A (en) * 2005-06-30 2007-10-16 Wyeth Corp Amino-5-(5-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation
BRPI0613578A2 (pt) 2005-06-30 2012-01-17 Wyeth Corp composito da fórmula i; uso de um composto de fórmula i; e composição farmacêutica
CN101238124A (zh) 2005-07-18 2008-08-06 默克公司 用于治疗阿尔茨海默氏病的螺哌啶β-分泌酶抑制剂
TW200730523A (en) 2005-07-29 2007-08-16 Wyeth Corp Cycloalkyl amino-hydantoin compounds and use thereof for β-secretase modulation
US20090042867A1 (en) 2005-08-11 2009-02-12 Klaus Fuchs Compounds for the treatment of alzheimer's disease
CA2618474A1 (fr) 2005-08-11 2007-02-15 Boehringer Ingelheim International Gmbh Composes pour le traitement de la maladie d'alzheimer
CA2618481A1 (fr) 2005-08-11 2007-02-15 Boehringer Ingelheim International Gmbh Composes utilises pour traiter la maladie d'alzheimer
WO2007017507A1 (fr) 2005-08-11 2007-02-15 Boehringer Ingelheim International Gmbh Inhibiteurs de la beta-secretase pour traiter la maladie d'alzheimer
WO2007021793A1 (fr) 2005-08-12 2007-02-22 Bristol-Myers Squibb Company Diaminopropanes macrocycliques comme inhibiteurs de la beta-secretase
US7601751B2 (en) 2005-09-01 2009-10-13 Bristol-Myers Squibb Company Indole acetic acid acyl guanidines as β-secretase inhibitors
EP2256107A1 (fr) * 2005-09-26 2010-12-01 Wyeth LLC Composés d'amino-5-[4-(difluorométhoxy)phényl]-5- phénylimidazolone comme inhibiteurs de la bêta-sécrétase (BACE)
WO2007047306A1 (fr) 2005-10-12 2007-04-26 Elan Pharmaceuticals, Inc. Methodes de traitement de l'amylose au moyen de derives aryl-cyclopropyle inhibiteurs d'aspartyl-proteases
WO2007047305A1 (fr) 2005-10-12 2007-04-26 Elan Pharmaceuticals, Inc. Procedes de traitement de l'amyloïdose en utilisant des derives de cyclopropyle inhibiteurs de l'aspartyle-protease
PL1966198T3 (pl) 2005-10-25 2011-07-29 Janssen Pharmaceutica Nv Pochodne 2-amino-3,4-dihydropirydo[3,4-d]pirymidyny do zastosowania jako inhibitory beta-sekretazy (BACE)
EP2597087B1 (fr) 2005-10-25 2016-03-30 Shionogi&Co., Ltd. Dérivés dihydrooxazine et tétrahydropyrimidine comme inhibiteurs de BACE 1
AR057983A1 (es) 2005-10-27 2008-01-09 Schering Corp Inhibidores hterociclicos de aspartil proteasas
PE20070798A1 (es) 2005-10-31 2007-08-24 Schering Corp Compuestos heterociclicos como inhibidores de aspartil proteasas
WO2007051333A1 (fr) 2005-11-02 2007-05-10 Oncalis Ag Inhibiteurs de beta-secretase a base de triazine
US20080255167A1 (en) 2005-11-15 2008-10-16 Jeffrey Albert Novel 2-Aminopyrimidine or 2-Aminiopyridinone Derivatives and Their Use
TW200804290A (en) 2005-11-15 2008-01-16 Astrazeneca Ab Compounds and uses thereof
EP1951682A4 (fr) 2005-11-15 2011-06-15 Astrazeneca Ab Novequx 2-aminopyrimidinone ou derives de 2-aminopyridinone et leur utilisation
WO2007058580A1 (fr) 2005-11-15 2007-05-24 Astrazeneca Ab Nouveaux derives de 2-aminopyrimidinone et leur utilisation
TW200734311A (en) 2005-11-21 2007-09-16 Astrazeneca Ab New compounds
US7838676B2 (en) 2005-11-21 2010-11-23 Amgen Inc. Beta-secretase modulators and methods of use
EP1971598A1 (fr) 2005-11-21 2008-09-24 Amgen Inc. Modulateurs de beta-secretase et procedes d'utilisation associes
WO2007058601A1 (fr) 2005-11-21 2007-05-24 Astrazeneca Ab Nouveaux composes 2-amino-imidazole-4-one et leur utilisation dans la fabrication d'un medicament destine a etre utilise dans le traitement d'une deficience cognitive, la maladie d'alzheimer, le neurodegenerescence et la demence
US7872009B2 (en) 2005-11-21 2011-01-18 Amgen Inc. Beta-Secretase modulators and methods of use
US7745484B2 (en) 2005-11-21 2010-06-29 Amgen Inc. Beta-secretase modulators and methods of use
CA2630459A1 (fr) 2005-11-22 2007-05-31 Pfizer Products Inc. Azacycloalcanes substitues pouvant etre employes dans le traitement d'etats pathologiques du snc
AR057579A1 (es) 2005-11-23 2007-12-05 Merck & Co Inc Compuestos espirociclicos como inhibidores de histona de acetilasa (hdac)
BRPI0620025A2 (pt) 2005-12-19 2011-10-25 Wyeth Corp composto, método para o tratamento de uma doença ou transtorno associado a atividade excessiva de bace, método para modular a atividade de bace, composição farmacêutica e uso do composto
AR058381A1 (es) 2005-12-19 2008-01-30 Astrazeneca Ab Compuestos derivados de 2-aminopiridin-4-onas y una composicion farmaceutica
GB0526614D0 (en) 2005-12-30 2006-02-08 Novartis Ag Organic compounds
EP1816122A3 (fr) 2006-01-19 2007-09-19 Speedel Experimenta AG Pipéridines substituées 3,4,5 en tant que composants thérapeutiques
WO2007092839A2 (fr) 2006-02-06 2007-08-16 Janssen Pharmaceutica N.V. DÉRIVÉS MACROCYCLIQUES UTILES COMME INHIBITEURS DE LA β-SÉCRÉTASE (BACE)
US7868022B2 (en) 2006-02-06 2011-01-11 Janssen Pharmaceutica Nv 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE)
US7776882B2 (en) 2006-02-06 2010-08-17 Baxter Ellen W 2-amino-3,4-dihydro-quinoline derivatives useful as inhibitors of β-secretase (BACE)
GB0602951D0 (en) 2006-02-14 2006-03-29 Novartis Ag Organic Compounds
WO2007100536A1 (fr) 2006-02-24 2007-09-07 Wyeth COMPOSES DE DIHYDROSPIRO[DIBENZO[A,D][7]ANNULENE-5,4'-IMIDAZOL] POUR L'INHIBITION DE LA β-SECRETASE
US7408071B2 (en) 2006-04-03 2008-08-05 Bristol-Myers Squibb Company N-aryl pyrrolidine derivatives as beta-secretase inhibitors
US20070232624A1 (en) * 2006-04-03 2007-10-04 Palumbo Joseph M Use of paliperidone for the treatment of sleep disturbances and/or excessive daytime sleepiness in psychiatric patients
US7390925B2 (en) 2006-04-03 2008-06-24 Bristol-Myers Squibb Company Oxime-containing acyl guanidines as beta-secretase inhibitors
JP2009532464A (ja) 2006-04-05 2009-09-10 アストラゼネカ・アクチエボラーグ ２−アミノピリミジン−４−オン及びＡβ−関連の病理を治療又は予防するためのその使用
TW200808751A (en) 2006-04-13 2008-02-16 Astrazeneca Ab New compounds
WO2007127108A1 (fr) 2006-04-21 2007-11-08 Wyeth Production d'intermédiaires de type aminoalcools purs du point de vue chiral, leurs dérivés et leurs utilisations
CN101484429A (zh) * 2006-06-12 2009-07-15 先灵公司 杂环的天冬氨酰基蛋白酶抑制剂
TW200808796A (en) * 2006-06-14 2008-02-16 Astrazeneca Ab New compounds III
TW200815447A (en) 2006-06-14 2008-04-01 Astrazeneca Ab Novel compounds IV
TW200815449A (en) 2006-06-14 2008-04-01 Astrazeneca Ab Novel compounds II
US20080051420A1 (en) 2006-06-14 2008-02-28 Astrazeneca Ab New Compounds 317
TW200815443A (en) 2006-06-14 2008-04-01 Astrazeneca Ab Novel compounds I
TW200815349A (en) 2006-06-22 2008-04-01 Astrazeneca Ab New compounds
CA2656869A1 (fr) 2006-07-20 2008-01-24 Novartis Ag Lactames macrocycliques
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
TW200817406A (en) 2006-08-17 2008-04-16 Wyeth Corp Imidazole amines as inhibitors of β-secretase
EP2064201A2 (fr) 2006-09-21 2009-06-03 Wyeth Indolylalkylpyridin-2-amines pour l'inhibition de la beta-secretase
WO2008045250A1 (fr) 2006-10-06 2008-04-17 Merck & Co., Inc. Inhibiteurs de spiropipéridine macrocyclique de bêta-secrétase pour le traitement de la maladie d'alzheimer
WO2008063114A1 (fr) 2006-11-20 2008-05-29 Astrazeneca Ab Amino-imidazolones et utilisation thérapeutique de ces composés pour traiter les troubles cognitifs, la maladie d'alzheimer, la neurodégénérescence et la démence
KR20090087487A (ko) 2006-12-12 2009-08-17 쉐링 코포레이션 아스파르틸 프로테아제 억제제
US7902218B2 (en) 2006-12-12 2011-03-08 Bristol-Myers Squibb Company Substituted tetrahydroisoquinolines as β-secretase inhibitors
US20100016341A1 (en) 2006-12-12 2010-01-21 Zhaoning Zhu Aspartyl protease inhibitors containing a tricyclic ring system
TW200831484A (en) 2006-12-20 2008-08-01 Astrazeneca Ab New compounds
TW200831091A (en) 2006-12-20 2008-08-01 Astrazeneca Ab New compounds
WO2008076043A1 (fr) 2006-12-20 2008-06-26 Astrazeneca Ab Nouveaux 2-amino-5,5-diaryl-imidazol-4-ones
CN101209976B (zh) 2006-12-29 2012-01-11 中国人民解放军军事医学科学院毒物药物研究所 取代的酒石酸衍生物及其用于制备β-分泌酶抑制剂的用途
JP2010515681A (ja) 2007-01-04 2010-05-13 メルク・シャープ・エンド・ドーム・コーポレイション アルツハイマー病治療用の二環式スピロピペリジンベータ−セクレターゼ阻害剤
MX2009008255A (es) 2007-02-02 2009-08-12 Hoffmann La Roche Nuevas 2-aminooxazolinas como ligandos taar1.
PE20090160A1 (es) 2007-03-20 2009-02-11 Wyeth Corp COMPUESTOS AMINO-5-[4-(DIFLUOROMETOXI)FENIL SUSTITUIDO]-5-FENILIMIDAZOLONA COMO INHIBIDORES DE ß-SECRETASA
CL2008000791A1 (es) 2007-03-23 2008-05-30 Wyeth Corp Compuestos derivados de 2-amino-5-(4-difluorometoxi-fenil)-5-fenil-imidazolidin-4-ona; composicion farmaceutica que comprende a dichos compuestos; y su uso en el tratamiento de una enfermedad asociada con la actividad bace excesiva, tales como enferm
CA2684470C (fr) 2007-04-16 2016-02-09 Hutchison Medipharma Enterprises Limited Derives de pyrimidine
WO2008133273A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Composition pharmaceutique pour le traitement de la maladie d'alzheimer
AU2008245082B8 (en) 2007-04-24 2012-09-13 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
TW200902499A (en) 2007-05-15 2009-01-16 Astrazeneca Ab New compounds
TW200902503A (en) 2007-05-15 2009-01-16 Astrazeneca Ab New compounds
WO2009005470A1 (fr) 2007-07-05 2009-01-08 Astrazeneca Ab Dérivés d'isoindole substitués aryle et hétéroaryle en tant qu'inhibiteurs de la bace
WO2009005471A1 (fr) 2007-07-05 2009-01-08 Astrazeneca Ab Dérivés d'isoindole substitués aryle et hétéroaryle en tant qu'inhibiteurs de la bace
JP5450407B2 (ja) 2007-07-06 2014-03-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 置換アミノ−キナゾリノン、前記化合物を含む薬物、それらの使用及び製造方法
WO2009013293A1 (fr) 2007-07-24 2009-01-29 Novartis Ag Cyclohexanecarboxamides substitués utiles comme inhibiteurs de bace
AU2009205072C1 (en) 2008-01-18 2016-10-13 Eisai R & D Management Co., Ltd. Condensed aminodihydrothiazine derivative
JP2011510030A (ja) 2008-01-22 2011-03-31 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 置換アミノ−ベンゾイミダゾール類、該化合物を含む医薬、これらの使用及びこれらの製造方法
JP2011510989A (ja) 2008-01-28 2011-04-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ β−セクレターゼ（ＢＡＣＥ）の阻害物質として有用な６−置換−チオ−２−アミノ−キノリン誘導体
AU2009209147B2 (en) 2008-01-29 2013-03-14 Janssen Pharmaceutica Nv 2-amino-quinoline derivatives useful as inhibitors of beta-secretase (BACE)
WO2009103626A1 (fr) 2008-02-18 2009-08-27 F. Hoffmann-La Roche Ag Dérivés de 4,5-dihydrooxazol-2-ylamine
CA2714058A1 (fr) 2008-02-28 2009-09-03 Ivory D. Hills Inhibiteurs de la 2-aminoimidazole beta-secretase utiles pour le traitement de la maladie d'alzheimer
EP2288613B1 (fr) 2008-04-22 2016-07-13 Merck Sharp & Dohme Corp. Composes de 2-imino-3-methyl-pyrrolo pyrimidinone substitues par phenyle utilises en tant qu inhibiteurs bace-1, compositions et utilisation associees
TWI431004B (zh) 2008-05-02 2014-03-21 Lilly Co Eli Ｂａｃｅ抑制劑
NZ588589A (en) 2008-05-05 2012-07-27 Pfizer Novel class of spiro piperidines for the treatment of neurodegenerative diseases
NZ589590A (en) 2008-06-13 2012-05-25 Shionogi & Co Sulfur-containing heterocyclic derivative having beta-secretase-inhibiting activity
EP2318416B1 (fr) 2008-07-28 2013-09-04 Eisai R&D Management Co., Ltd. Derives de spiroaminodihydrothiazine
WO2010013302A1 (fr) 2008-07-28 2010-02-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de spiroaminodihydrothiazine
TWI385175B (zh) 2008-09-11 2013-02-11 Amgen Inc 作為β-分泌酶調節劑之螺旋-三環化合物及其使用方法
AU2009300836B2 (en) 2008-09-30 2014-02-27 Eisai R&D Management Co., Ltd. Novel fused aminodihydrothiazine derivative
WO2010042030A1 (fr) 2008-10-07 2010-04-15 Medivir Ab Inhibiteurs d'aspartyl protéase
EP2349244A4 (fr) 2008-10-10 2012-09-19 Comentis Inc Composes de pyrrolidine qui empeche l'activite beta-secretase et procedes pour leur utilisation
EP2360155A4 (fr) 2008-10-22 2012-06-20 Shionogi & Co 2-aminopyridin-4-one et dérivé de 2-aminopyridine dont l'activité inhibe la bace1
US20100125081A1 (en) 2008-11-14 2010-05-20 Astrazeneca Ab New compounds 574
US8394807B2 (en) 2008-11-20 2013-03-12 Purdue Research Foundation Quinazoline inhibitors of BACE 1 and methods of using
JP2012525389A (ja) 2009-04-27 2012-10-22 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー 置換イソキノリン誘導体、医薬組成物、及びβ−セクレターゼ阻害剤としての使用方法
BRPI1012697A2 (pt) 2009-04-27 2016-03-29 High Point Pharmaceuticals Llc derivados imidazo[1,2-a]piridina substituídos, composições farmacêuticas, e métodos de uso como inibidores da b-secretase
AR077277A1 (es) 2009-07-09 2011-08-17 Lilly Co Eli Compuestos de biciclo (1,3)tiazin-2-amina formulacion farmaceutica que lo comprende y su uso para la manufactura de un medicamento util para el tratamiento de la enfermedad de alzheimer
GB0912778D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydro-oxazine derivatives
GB0912777D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydropyrimidone derivatives
UY32799A (es) 2009-07-24 2011-02-28 Novartis Ag Derivados de oxazina y su uso en el tratamiento de trastornos neurológicos
US8188079B2 (en) 2009-08-19 2012-05-29 Hoffman-La Roche Inc. 3-amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines
WO2011044057A1 (fr) 2009-10-05 2011-04-14 Comentis, Inc. Composés sulfonamido pyrrolidine qui inhibent l'activité bêta sécrétase et procédés d'utilisation associés
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
UA108363C2 (uk) 2009-10-08 2015-04-27 Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування
EP2485920B1 (fr) 2009-10-08 2016-04-27 Merck Sharp & Dohme Corp. Composés hétérocycliques iminopentafluorosoufrés en tant qu'inhibiteurs de bace-1, compositions et leur utilisation
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US8822485B2 (en) 2009-11-23 2014-09-02 Amgen Inc. Amino heteroaryl compounds as beta-secretase modulators and methods of use
EP2504315A1 (fr) 2009-11-23 2012-10-03 Amgen Inc. Composés amino hétéroaryles comme modulateurs de la bêta-secrétase et procédés d'utilisation
WO2011071109A1 (fr) 2009-12-11 2011-06-16 塩野義製薬株式会社 Composé hétérocyclique fusionné comportant un groupement amino
CN102834384A (zh) 2009-12-11 2012-12-19 盐野义制药株式会社 *嗪衍生物
US20120258961A1 (en) 2009-12-24 2012-10-11 Shionogi & Co., Ltd. 4-amino-1,3-thiazine or oxazine derivative
US8883782B2 (en) 2010-03-15 2014-11-11 Amgen Inc. Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use
EP2547686B1 (fr) 2010-03-15 2014-01-22 Amgen Inc. Composés spirannique de amino-dihydrooxazine et amino-dihydrothiazine comme modulateur de bêta-sécrétase et leur utilisation médicale

Cited By (170)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8937093B2 (en) 2003-12-15 2015-01-20 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US7700603B2 (en) 2003-12-15 2010-04-20 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8242112B2 (en) 2003-12-15 2012-08-14 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US9416108B2 (en) 2003-12-15 2016-08-16 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US7592348B2 (en) 2003-12-15 2009-09-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7973067B2 (en) 2003-12-15 2011-07-05 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8722708B2 (en) 2005-06-14 2014-05-13 Merck Sharp & Dohme Inc. Substituted isoindolines as aspartyl protease inhibitors
US7868000B2 (en) 2005-06-14 2011-01-11 Schering Corporation Aspartyl protease inhibitors
US9382242B2 (en) 2005-06-14 2016-07-05 Merck Sharp & Dohme Corp. Preparation and use of compounds as protease inhibitors
US8173642B2 (en) 2005-10-25 2012-05-08 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8546380B2 (en) 2005-10-25 2013-10-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8815851B2 (en) 2005-10-25 2014-08-26 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8633188B2 (en) 2005-10-25 2014-01-21 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US9029358B2 (en) 2005-10-25 2015-05-12 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US20120232064A1 (en) * 2006-06-12 2012-09-13 Schering Corporation Aspartyl protease inhibitors
US8629155B2 (en) 2006-06-12 2014-01-14 Merck Sharp & Dohme, Corp. Aspartyl protease inhibitors
US8168641B2 (en) 2006-06-12 2012-05-01 Schering Corporation Aspartyl protease inhibitors
US8691833B2 (en) 2007-02-23 2014-04-08 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US8691831B2 (en) 2007-02-23 2014-04-08 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US8829036B2 (en) 2007-02-23 2014-09-09 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US8895548B2 (en) 2007-04-24 2014-11-25 Shionogi & Co., Ltd. Pharmaceutical composition for treating alzheimer's disease
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8168630B2 (en) 2007-04-24 2012-05-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8884062B2 (en) 2007-04-24 2014-11-11 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8541427B2 (en) 2008-04-22 2013-09-24 Merck, Sharp & Dohme, Corp. Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use
US8450331B2 (en) 2008-04-22 2013-05-28 Merck Sharp & Dohme Corp. Thiophenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use
US9650371B2 (en) 2008-06-13 2017-05-16 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
WO2009151098A1 (fr) 2008-06-13 2009-12-17 塩野義製薬株式会社 DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DU SOUFRE AYANT UNE ACTIVITÉ INHIBANT LA β-SÉCRÉTASE
US9273053B2 (en) 2008-06-13 2016-03-01 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having Beta secretase inhibitory activity
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US9451775B2 (en) 2008-07-17 2016-09-27 Bayer Intellectual Property Gmbh Heterocyclic compounds as pesticides
WO2010006713A3 (fr) * 2008-07-17 2011-04-14 Bayer Cropscience Ag Composés hétérocycliques utilisés comme pesticides
US8809547B2 (en) 2008-07-17 2014-08-19 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US8450308B2 (en) 2008-08-19 2013-05-28 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8426447B2 (en) 2008-09-11 2013-04-23 Amgen Inc. Spiro-tricyclic ring compounds as beta-secretase modulators and methods of use
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US20110275608A1 (en) * 2009-01-12 2011-11-10 Array Biopharma Inc. Piperidine-containing compounds and use thereof
US8809538B2 (en) * 2009-01-12 2014-08-19 Array Biopharma Inc. Piperidine-containing compounds and use thereof
EP2801570A1 (fr) 2009-03-13 2014-11-12 Vitae Pharmaceuticals, Inc. Inhibiteurs de la bêta-sécrétase
WO2010105179A3 (fr) * 2009-03-13 2010-11-11 Vitae Pharmaceuticals, Inc. Inhibiteurs de bêta-sécrétase
US8633212B2 (en) 2009-03-13 2014-01-21 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9212153B2 (en) 2009-03-13 2015-12-15 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
WO2010105179A2 (fr) 2009-03-13 2010-09-16 Vitae Pharmaceuticals, Inc. Inhibiteurs de bêta-sécrétase
AP2866A (en) * 2009-03-13 2014-03-31 Vitae Pharmaceuticals Inc Inhibitors of beta-secretase
US10336717B2 (en) 2009-03-13 2019-07-02 Vitae Pharmaceuticals, Llc Inhibitors of beta-secretase
JP2012520324A (ja) * 2009-03-13 2012-09-06 ヴァイティー ファーマシューティカルズ，インコーポレイテッド β−セクレターゼ阻害剤
EA020875B1 (ru) * 2009-03-13 2015-02-27 Вайтаи Фармасьютиклз, Инк. Ингибиторы бета-секретазы
US10265311B2 (en) 2009-07-22 2019-04-23 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10369144B2 (en) 2009-07-22 2019-08-06 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10695339B2 (en) 2009-07-22 2020-06-30 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10369143B2 (en) 2009-07-22 2019-08-06 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10238643B2 (en) 2009-07-22 2019-03-26 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US20140206675A1 (en) * 2009-10-08 2014-07-24 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
WO2011044181A1 (fr) 2009-10-08 2011-04-14 Schering Corporation Composés de dioxyde d'iminothiadiazine comme inhibiteurs de bace, compositions et leur utilisation
WO2011044187A1 (fr) 2009-10-08 2011-04-14 Schering Corporation Composés de type dioxyde d'imino-thiadiazine utilisés en tant qu'inhibiteurs de bace, compositions en contenant et leur utilisation
WO2011044185A2 (fr) 2009-10-08 2011-04-14 Schering Corporation Composés hétérocycliques iminopentafluorosoufrés en tant qu'inhibiteurs de bace-1, compositions et leur utilisation
US20140296221A1 (en) * 2009-10-08 2014-10-02 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US20140296222A1 (en) * 2009-10-08 2014-10-02 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
EP3034080A1 (fr) 2009-10-08 2016-06-22 Merck Sharp & Dohme Corp. Composés de dioxyde iminothiadiazine en tant qu'inhibiteurs de bace, compositions et leur utilisation
US9687494B2 (en) 2009-10-08 2017-06-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US9428475B2 (en) * 2009-10-08 2016-08-30 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
EP2485920A4 (fr) * 2009-10-08 2013-04-24 Merck Sharp & Dohme Composés hétérocycliques iminopentafluorosoufrés en tant qu'inhibiteurs de bace-1, compositions et leur utilisation
US9475785B2 (en) 2009-10-08 2016-10-25 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US8940748B2 (en) * 2009-10-08 2015-01-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9029362B2 (en) * 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
US9290466B2 (en) 2009-12-11 2016-03-22 Shionogi & Co., Ltd. Oxazine derivatives
WO2011071135A1 (fr) 2009-12-11 2011-06-16 塩野義製薬株式会社 Dérivé d'oxazine
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9656974B2 (en) 2009-12-11 2017-05-23 Shionogi & Co., Ltd. Oxazine derivatives
US9045500B2 (en) 2010-02-24 2015-06-02 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9012446B2 (en) 2010-03-15 2015-04-21 Amgen Inc. Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
WO2011115928A1 (fr) 2010-03-15 2011-09-22 Amgen Inc. Composés spiro de l'amino-dihydrooxazine et de l'amino-dihydrothiazine en tant que modulateurs de la béta-sécrétase et utilisation médicale associée
US8497264B2 (en) 2010-03-15 2013-07-30 Amgen Inc. Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
WO2011115938A1 (fr) 2010-03-15 2011-09-22 Amgen Inc. Composés spiro tétracycliques en tant que modulateurs de la béta-sécrétase
US8883782B2 (en) 2010-03-15 2014-11-11 Amgen Inc. Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use
WO2012019056A1 (fr) 2010-08-05 2012-02-09 Amgen Inc. Composés d'amino-iso-indole, d'amino-aza-iso-indole, d'amino-dihydro-isoquinoléine et d'amino-benzoxazine en tant que modulateurs de la bêta-sécrétase et leurs méthodes d'utilisation
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
WO2012071279A1 (fr) 2010-11-23 2012-05-31 Amgen Inc. Spiro-amino-imidazolones et spiro-amino-dihydro-pyrimidinones en tant que modulateurs de bêta-sécrétase et leurs méthodes d'utilisation
US9346827B2 (en) 2011-02-07 2016-05-24 Amgen Inc. 5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use
WO2012109165A1 (fr) 2011-02-07 2012-08-16 Amgen Inc. Composés de 5-amino-oxazépine et 5-amino-thiazépane en tant qu'antagonistes de la bêta-sécrétase et leurs procédés d'utilisation
WO2012112462A1 (fr) 2011-02-15 2012-08-23 Amgen Inc. Composés hétérocycliques spiro-amino-imidazo-condensés en tant que modulateurs de la bêta-secrétase et méthodes d'utilisation
US8962859B2 (en) 2011-02-15 2015-02-24 Amgen Inc. Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
WO2012138734A1 (fr) 2011-04-07 2012-10-11 Merck Sharp & Dohme Corp. Composés de dioxyde de thiadiazine condensés avec des dérivés oxacycliques en c5-c6 comme inhibiteurs de bace, compositions, et utilisation use
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9499502B2 (en) 2011-04-13 2016-11-22 Merck Sharp & Dohme Corp. 5-substituted iminothiazines and their mono- and dioxides as BACE inhibitors, compositions, and their use
WO2013028670A1 (fr) 2011-08-22 2013-02-28 Merck Sharp & Dohme Corp. Iminothiazines 2-spiro-substituées et leur mono- et dioxydes en tant qu'inhibiteurs bace, compositions et leur utilisation
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9296759B2 (en) 2011-09-21 2016-03-29 Amgen Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
WO2013044092A1 (fr) 2011-09-21 2013-03-28 Amgen Inc. Composés d'amino-oxazines et d'amino-dihydrothiazine comme modulateurs de sécrétase bêta et procédés d'utilisation
US9777019B2 (en) 2011-09-21 2017-10-03 Amgen Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
US8981112B2 (en) 2012-03-05 2015-03-17 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9949975B2 (en) 2012-03-05 2018-04-24 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9526727B2 (en) 2012-03-05 2016-12-27 Vitae Pharmaceutical, Inc. Inhibitors of beta-secretase
EP3607946A1 (fr) 2012-03-19 2020-02-12 Buck Institute for Research on Aging Inhibiteurs de bace spécifiques app (asbis) et leurs utilisations
US9018391B2 (en) 2012-08-27 2015-04-28 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
WO2014062553A1 (fr) 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Composés de dioxyde de thiadiazine substituée tricyclique utilisés en tant qu'inhibiteurs de bace, compositions et leur utilisation
US9416129B2 (en) 2012-10-17 2016-08-16 Merck Sharp & Dohme Corp. Tricyclic substituted thiadiazine dioxide compounds as BACE inhibitors, compositions and their use
WO2014062549A1 (fr) 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Composés de dioxyde de thiadiazine substitués tricycliques en tant qu'inhibiteurs de bace, compositions et leur utilisation
US9422277B2 (en) 2012-10-17 2016-08-23 Merck Sharp & Dohme Corp. Tricyclic substituted thiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9725469B2 (en) 2012-11-15 2017-08-08 Amgen, Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
WO2014078314A1 (fr) 2012-11-15 2014-05-22 Amgen Inc. Composés d'amino-oxazine et d'amino-dihydrothiazine jouant le rôle de modulateurs de bêta-sécrétase et procédés d'utilisation
US9447085B2 (en) 2012-12-14 2016-09-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxides containing a thioamide, amidine, or amide oxime group as BACE inhibitors, compositions, and their use
US9489013B2 (en) 2012-12-20 2016-11-08 Merck Sharp & Dohme Corp. C6-azaspiro iminothiadiazine dioxides as bace inhibitors, compositions, and their use
US9365589B2 (en) 2012-12-20 2016-06-14 Merck Sharp & Dohme Corp. C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9580396B2 (en) 2012-12-21 2017-02-28 Merck Sharp & Dohme Corp. C6-spiro iminothiadiazine dioxides as BACE inhibitors, compositions, and their use
EP3653609A1 (fr) 2013-02-12 2020-05-20 Buck Institute for Research on Aging Hydantoïnes modulant le traitement de précurseur du peptide amyloïde (app) à médiation par bêta-secrétase (bace)
WO2014127881A1 (fr) 2013-02-25 2014-08-28 Merck Patent Gmbh Dérivés de 2-amino-3,4-dihydroquinazoline et leur utilisation comme inhibiteurs de la cathepsine d
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9353089B2 (en) 2013-03-26 2016-05-31 Saint Louis University Compositions and methods for the treatment of malaria
US9725468B2 (en) 2013-09-13 2017-08-08 Merck Sharp & Dohme Corp. C5-spiro iminothiazine dioxides as BACE inhibitors, compositions, and their use
US9802928B2 (en) 2013-12-18 2017-10-31 Merck Sharp & Dohme Corp. C-6 spirocarbocyclic iminothiadiazine dioxides as BACE inhibitors, compositions, and their use
US9745324B2 (en) 2013-12-18 2017-08-29 Merck Sharp & Dohme Corp. Iminothiadiazepane dioxide compounds as BACE inhibitors, compositions, and their use
KR20160141849A (ko) 2014-04-11 2016-12-09 시오노기세이야쿠가부시키가이샤 Bace1 저해 작용을 갖는 디하이드로티아진 및 디하이드로옥사진 유도체
WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2016172255A1 (fr) * 2015-04-21 2016-10-27 Allgenesis Biotherapeutics, Inc. Composés et leur utilisation en tant qu'inhibiteurs de bace1
EP3250035A4 (fr) * 2015-04-21 2019-02-27 Allgenesis Biotherapeutics Inc. Composés et leur utilisation en tant qu'inhibiteurs de bace1
US10870635B2 (en) 2015-04-21 2020-12-22 Allgenesis Biotherapeutics, Inc. Compounds and their use as BACE1 inhibitors
WO2017061534A1 (fr) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dérivés de dihydrothiazine
US11136310B2 (en) 2015-11-25 2021-10-05 UCB Biopharma SRL Iminotetrahydropyrimidinone derivatives as plasmepsin V inhibitors
EA034196B1 (ru) * 2015-11-25 2020-01-16 Юсб Байофарма Спрл Производные иминотетрагидропиримидинона в качестве ингибиторов плазмепсина v
WO2017089453A1 (fr) 2015-11-25 2017-06-01 Ucb Biopharma Sprl Dérivés d'iminotétrahydropyrimidinone utilisés comme inhibiteurs de plasmepsine v
US11766435B2 (en) 2016-02-18 2023-09-26 Merck Sharp & Dohme Llc N3-substituted iminopyrimidinones as antimalarial agents
EP3416645A4 (fr) * 2016-02-18 2019-10-16 Merck Sharp & Dohme Corp. Composés pour le traitement du paludisme
EP3416647A4 (fr) * 2016-02-18 2019-10-23 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
WO2017144517A1 (fr) 2016-02-23 2017-08-31 Ucb Biopharma Sprl Dérivés de dioxyde d'iminothiadiazinane utilisés comme inhibiteurs de la plasmepsine v
US10464932B2 (en) 2016-02-23 2019-11-05 Ucb Biopharma Sprl Iminothiadiazinane dioxide derivatives as plasmepsin V inhibitors
WO2018033455A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US10696639B2 (en) 2016-12-06 2020-06-30 Merck Sharp & Dohme Corp. Heterocyclic compounds as HIV protease inhibitors
WO2018106519A1 (fr) * 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques en tant qu'inhibiteurs de la protéase du vih
US20200069691A1 (en) * 2016-12-22 2020-03-05 Merck Sharp & Dohme Corp. Heterocyclic compounds as hiv protease inhibitors
EP3558285A4 (fr) * 2016-12-22 2020-09-09 Merck Sharp & Dohme Corp. Composés hétérocycliques utiles en tant qu'inhibiteurs de la protéase du vih
WO2018118829A1 (fr) * 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Composés hétérocycliques en tant qu'inhibiteurs de la protéase du vih
WO2018118827A1 (fr) * 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Composés hétérocycliques utiles en tant qu'inhibiteurs de la protéase du vih
CN106810458B (zh) * 2016-12-31 2019-05-03 武汉工程大学 一种拆分dl-2-氨基丙醇制备l-2-氨基丙醇的方法
CN106810458A (zh) * 2016-12-31 2017-06-09 武汉工程大学 一种拆分dl‑2‑氨基丙醇制备l‑2‑氨基丙醇的方法
KR20200071098A (ko) * 2017-10-13 2020-06-18 길리애드 사이언시즈, 인코포레이티드 Hiv 프로테아제 억제제로서의 1-벤질-2-이미노-4-페닐-5-옥소이미다졸리딘 유도체
WO2019192992A1 (fr) 2018-04-06 2019-10-10 Ucb Biopharma Sprl Analogues d'hexahydropyrimidine antipaludiques
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity
US11890378B2 (en) 2018-09-28 2024-02-06 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US10925832B2 (en) 2018-09-28 2021-02-23 Karuna Therapeutics, Inc. Compositions and methods for treatment of disorders ameliorated by muscarinic receptor activation
US11471413B2 (en) 2018-09-28 2022-10-18 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US10933020B2 (en) 2018-09-28 2021-03-02 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US11452692B2 (en) 2018-09-28 2022-09-27 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
WO2020214716A1 (fr) * 2019-04-17 2020-10-22 Gilead Sciences, Inc. Inhibiteurs de la protéase du vih à base de 2-imino-5-oxo-imidazolidine
US11318119B2 (en) 2019-04-17 2022-05-03 Gilead Sciences, Inc. HIV protease inhibitors
WO2020229427A1 (fr) 2019-05-14 2020-11-19 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques
WO2021026884A1 (fr) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Agents antipaludiques
US12350270B2 (en) 2019-08-15 2025-07-08 Msd R&D (China) Co. Ltd. Antimalarial agents
CN114555564A (zh) * 2019-08-15 2022-05-27 默沙东公司 抗疟药
CN114555564B (zh) * 2019-08-15 2024-01-30 默沙东公司 抗疟药
WO2021027502A1 (fr) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Agents antipaludiques
WO2021032687A1 (fr) 2019-08-19 2021-02-25 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques
WO2021101836A1 (fr) * 2019-11-19 2021-05-27 Merck Sharp & Dohme Corp. Agents antipaludiques
US12338219B2 (en) 2019-11-19 2025-06-24 Merch Sharpe & Dohme LLC Antimalarial agents
WO2021155612A1 (fr) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Agents antipaludiques
WO2021155791A1 (fr) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Agents antipaludiques
WO2022008639A1 (fr) 2020-07-10 2022-01-13 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques
WO2023102747A1 (fr) * 2021-12-07 2023-06-15 Merck Sharp & Dohme Llc Agents antipaludiques
WO2023152042A1 (fr) 2022-02-08 2023-08-17 UCB Biopharma SRL Analogues d'hexahydropyrimidine antipaludiques

Also Published As

Publication number Publication date
RU2009135277A (ru) 2011-03-27
PT2097387T (pt) 2016-07-20
US20080200445A1 (en) 2008-08-21
AU2008219071B2 (en) 2013-03-28
MX2009009063A (es) 2010-01-29
TW200840580A (en) 2008-10-16
US8183252B2 (en) 2012-05-22
SG179407A1 (en) 2012-04-27
US20120276118A1 (en) 2012-11-01
US8829036B2 (en) 2014-09-09
ECSP099597A (es) 2009-09-29
HRP20160876T1 (hr) 2016-09-23
RS54979B1 (sr) 2016-11-30
CO6220968A2 (es) 2010-11-19
ES2582367T3 (es) 2016-09-12
EP2097387B1 (fr) 2016-05-04
KR20090114468A (ko) 2009-11-03
TWI355937B (en) 2012-01-11
JP2013014628A (ja) 2013-01-24
CA2678958A1 (fr) 2008-08-28
CA2678958C (fr) 2014-10-14
WO2008103351A3 (fr) 2009-07-23
ZA200905837B (en) 2012-01-25
JP5340177B2 (ja) 2013-11-13
AU2008219071A1 (en) 2008-08-28
DK2097387T3 (en) 2016-08-15
US8691831B2 (en) 2014-04-08
MY149183A (en) 2013-07-31
AU2008219071A2 (en) 2010-11-25
CL2008000531A1 (es) 2008-09-22
US20120231017A1 (en) 2012-09-13
AR065421A1 (es) 2009-06-03
HUE029867T2 (en) 2017-04-28
CN101715442B (zh) 2014-03-26
JP2010519254A (ja) 2010-06-03
RU2496774C2 (ru) 2013-10-27
TW201139415A (en) 2011-11-16
CN101715442A (zh) 2010-05-26
PE20100731A1 (es) 2010-11-12
US20100292203A1 (en) 2010-11-18
AR106237A2 (es) 2017-12-27
SI2097387T1 (sl) 2016-09-30
US7763609B2 (en) 2010-07-27
LT2097387T (lt) 2016-10-10
NZ579301A (en) 2012-05-25
CY1117946T1 (el) 2017-05-17
HK1130792A1 (zh) 2010-01-08
US8691833B2 (en) 2014-04-08
ME02528B (fr) 2017-02-20
IL200561A0 (en) 2010-05-17
BRPI0807547A2 (pt) 2014-06-17
KR101612961B1 (ko) 2016-04-19
EP2097387A2 (fr) 2009-09-09
IL200561A (en) 2015-03-31
PL2097387T3 (pl) 2016-11-30
US20120231018A1 (en) 2012-09-13
PE20081884A1 (es) 2008-12-27

Similar Documents

Publication Publication Date Title
DK2097387T3 (en) HETEROCYCLIC ASPARTYL PROTEASE INHIBITORS
US7973067B2 (en) Heterocyclic aspartyl protease inhibitors
EP1838304B1 (fr) Inhibiteurs d'aspartyle protease heterocycliques
EP2343069A1 (fr) Inhibiteurs heterocycliques d'aspartyl protease
HK1130792B (en) Heterocyclic aspartyl protease inhibitors
AU2013201438A1 (en) Heterocyclic aspartyl protease inhibitors
HK1106430B (en) Heterocyclic aspartyl protease inhibitors
HK1154507A (en) Heterocyclic aspartyl protease inhibitors

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880013100.0

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2008714220

Country of ref document: EP

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08714220

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2008219071

Country of ref document: AU

Ref document number: 12009501605

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2678958

Country of ref document: CA

Ref document number: 2009550601

Country of ref document: JP

Ref document number: 09088065

Country of ref document: CO

Ref document number: 4921/CHENP/2009

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 200561

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: MX/A/2009/009063

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 579301

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2008219071

Country of ref document: AU

Date of ref document: 20080220

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020097019655

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2009135277

Country of ref document: RU

ENP Entry into the national phase

Ref document number: PI0807547

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090824

WWE Wipo information: entry into national phase

Ref document number: P-2016/0558

Country of ref document: RS